1-arylsulphonyl, arylcarbonyl and 1-arylphosphonyl-3-phenyl-1,4,5,6-tetrahydropyridazines

ABSTRACT

Disclosed are progestin agonists having the following formula: ##STR1## W is absent or --CH═CH--; R 1  are independently selected from the group consisting of halogen, --CF 3 , and NO 2 , or both R 1  may be joined to form a bi-radical which is --CH═CHCH═CH--; 
     R 3  are independently selected from the group consisting of hydrogen, C 1-6  branched or linear alkyl, halogen and --CF 3 , with the proviso that R 3  at the 3-position must be H where R 3  at the 4-position is H, or both R 3  may be joined to form a bi-radical selected from the group consisting of --CH═CHCH═CH--, --C(NC 1-4  alkyl 2 )=CHCH═CH-- and --(CH 2 ) 4  --; 
     R 5  is selected from the group consisting of H and Me; 
     with the proviso that only one of R 1  and R 3  forms the fused bi-radical; and the stereoisomers.

This application is a 371 of PCT/US93/06394 filed Jul. 1, 1993, which isa continuation-in-part of U.S. Ser. No. 08/080,986 filed Jun. 21, 1993,now abandoned, which is a continuation of U.S. Ser. No. 07/906,984,filed Jul. 1, 1992, now abandoned.

FIELD OF THE INVENTION

The invention relates to novel 1-phenylsulphonyl, phenylcarbonyl and1-phenylphosphenyl-3-phenyl-1,4,5,6-tetrahydropyridazine compounds, andto novel methods for preparing the compounds. The novel compounds areuseful as contraceptives and in the treatment of osteoporosis. Theinvention further relates to pharmaceutical compositions in which acompound of the present invention is the active ingredient.

BACKGROUND OF THE INVENTION

The unacylated 3-phenyl-1,4,5,6-tetrahydropyridazine, A, is described byJ.-L. Aubagnac et al., Bull. Chem. Soc. France, 7, 2868, (1972). Anumber of 1-acylated derivatives of 1 are also disclosed. ##STR2##

W. Jones et al., J. Het. Chem., 21, 889 (1984) disclose that thethiocarbamoylation of A with methyl isothiocyanate produces thecorresponding thiocarbamide derivative, B. No biological activity isdisclosed. ##STR3##

S. J. Clarke et al., J. Chem. Research, (S) 310 (1985) disclosecarbamate, carbamide and para-toulene sulfonamide derivatives of A.(sulfonamide derivative is C), which are prepared via cycloadditionreactions. Again, no biological activity is disclosed.

    ______________________________________                                         ##STR4##                                                                     R.sup.1     R.sup.3                                                                             R.sup.4     R.sup.5                                                                            R.sup.6                                    ______________________________________                                        H           H     H           OEt  H                                          H           H     Me          OEt  H                                          H           Me    H           OEt  H                                          H           H     H           OMe  Me                                         NO.sub.2    H     H           OEt  H                                          NO.sub.2    H     H           OMe  Me                                         Br          H     H           OEt  H                                          Br          H     Me          OEt  H                                          Br          Me    H           OEt  H                                          Br          H     H           OMe  Me                                         ______________________________________                                    

R. Faragher et al., in J. Chem. Soc. Perkin Trans, I, 249 (1979),disclose para-toulene sulfonamide and carbamate derivatives of A,(sulfonamide derivative is 4) which compounds are also prepared bycycloaddition reactions. As above, no biological activity is disclosed.##STR5##

Kalyanam et al., Synthetic Communications, 18 (16 & 17), (1988) disclosecompounds of the formula: ##STR6## wherein n is 1 or 2, as beingantiamoebics.

SUMMARY OF THE INVENTION

Briefly, according to the present invention, there are providedpreferred progestin agonists of the general formula: ##STR7## W isabsent or --CH═CH--; R¹ are independently selected from the groupconsisting of halogen, --CF₃, and NO₂, or both R¹ may be joined to forma bi-radical which is --CH═CHCH═CH--;

R³ are independently selected from the group consisting of hydrogen,C₁₋₆ branched or linear alkyl, halogen and --CF₃, with the proviso thatR³ at the 3-position must be H where R³ at the 4-position is H, or bothR³ may be joined to form a bi-radical selected from the group consistingof --CH═CHCH═CH--, --C(NC₁₋₄ alkyl₂)=CHCH═CH-- and --(CH₂)₄ --;

R⁵ is selected from the group consisting of H and Me;

with the proviso that only one of R¹ and R³ forms the fused bi-radical;and the stereoisomers.

Also provided by the present invention are preferred progestinantagonists of the general formula: ##STR8## W is absent or --CH═CH--;R¹ is selected from the group consisting of halogen, --CF₃ and --NO₂, orboth R¹ may be joined to form a bi-radical which is --CH═CHCH═CH--;

R³ is hydrogen, halogen, --CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, carboxy C₁₋₄alkyl and C₁₋₄ alkoxy carbonyl C₁₋₄ alkoxy with the proviso that R³ atthe 2-position is not hydrogen, or R³ may be joined to form a bi-radicalwhich is --CH═CHCH═CH-- attached at the 2- and 3-positions;

R^(a) are independently selected from hydrogen or halogen with theproviso that each may be halogen where R³ is selected only from halogen;

R⁵ is selected from the group consisting of hydrogen and methyl, oralternatively, R⁵ may be joined with the 6-position hydrogen to form abi-radical which is (5)-CH₂ CH═CH-(6);

with the proviso that only one of R¹, R³ and R⁵ forms the fusedbi-radical; and the steroisomers and pharmaceutically acceptable saltsand esters thereof.

Also provided by the present invention are preferred compounds useful topromote bone cell gowth, said compounds having the general formula:##STR9## Y is O or S; R³ is hydrogen or halogen with the proviso that atleast two R³ are halogen;

R⁵ is H or Me;

and the steroisomers thereof.

4. DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may be manufactured in what isbasically a two step process. In the first step and as demonstrated inschemes 1 and 2, a 3-phenyl-1,4,5,6-tetrahydropyridazine intermediate isformed. In the second step and as demonstrated in scheme 3, this3-phenyl-1,4,5,6-tetrahydropyridazine intermediate is joined at the1-position with the appropriately substituted phenyl or thienyl moiety.In special cases, and as exemplified in scheme 4, more advantageousprocesses are available for certain substitution patterns. Of course,the substituents on the final compounds may be obtained by starting withthe appropriately substituted starting materials or by modifyingprecursor substituents on an intermediate or final compound. Personsskilled in the art upon understanding the particular reactions suggestedherein will be readily able to determine how best to obtain a givensubstituent.

The substituents R^(1*), R^(3*) and R^(5*) as employed in Schemes 1-4are intended to include not only the substituents of R¹, R³ and R⁵ asgiven above for the preferred compounds, but also to include othersubstituents on their respective rings of compounds disclosed herein.Subscripts w, y and z as employed in these same schemes have valuesranging from 0-5, 0-3 and 0-5 respectively and are intended to show thatnot just the the substitution patterns of the preferred compounds asdescribed above may be made by this method, but that compounds withvarious substitution patterns may be made. Finally, Schemes 1-4 areexemplified employing phenyl as the ultimate 3-position substituent on1,4,5,6-tetrahydropyridazine. In each scheme, a starting material inwhich phenyl is replaced by the appropriate thienyl would ultimatelyproduce, by the same method, a 3-thienyl substituent on the1,4,5,6-tetrahydropyridazine, Thus, although Schemes 1-4 exemplify themanufacture of the 3-phenyl substituent, the 3-thienyl substituent issimilarly produced.

Referring to scheme 1, 3-phenyl-1,4,5,6-tetrahydropyridazine,intermediate 1-C, is formed in two reaction steps, In a first additionreaction, diketone starting material 1-A is refluxed in an alcoholsolvent with an excess of hydrazine to give the 6-oxo compound 1-B.Suitable alcohol solvents include methanol, ethanol, etc., with thereflux carried out for from 1 to 24 hours. This addition is furtherdescribed by S. Gabriel et al., Ber., 32, 395 (1879), W. Curran et al.,J. Med. Chem., 17(3), 273 (1974) and in U.S. Pat. Nos. 4,766,118 and4,721,784, which are incorporated herein by reference. Subsequently,6-oxo compound 1-B is reduced to intermediate 1-C in the presence of areducing agent Suitable reducing agents include diborane, lithiumaluminum hydride and di-i-butyl aluminum hydride. Where lithium aluminumhydride is employed, the reaction should be carried out at reducedtemperatures in a solvent such as THF. This reduction is furtherdescribed by J. L. Aubagnac et al., Bull. Chem. Soc. France, 2859(1972). Of course, it is clear that intermediate 1-C cannot have R_(5*)as a 6-position substituent. ##STR10##

Referring to Scheme 2, 3-phenyl-1,4,5,6-tetrahydropyridazine,intermediate 2-C, is formed in four reaction steps. In a first reaction,the appropriate phosphonium salt is deprotonated in ethereal solvent(ether, tetrahydrofuran, dioxane) with strong base (such asalkyllithium, sodium or potassium hydride or lithium diisopropyl amide)and stirred at low temperature under an atmosphere of inert gas. Thealdehyde 2-A is added to the cold solution and the mixture stirred forseveral hours at room temperature. Excess reagent is quenched (withwater or an alcohol), and the solution is filtered, dried over Na₂ SO₄(or MgSO₄, CaCl₂, CaSO₄, K₂ CO₃, or other similar drying agent),filtered again, and solvent is removed to give the diene 2-A' which isused without further purification. In a second step, 4-phenylurazole isdissolved in DMSO and cooled in a dry apparatus. Tosylisocyanate isadded as an oxidant and stirring continued. The diene 2-A' is added neatand the reaction continued for about 30 min. The solution is poured intoa halogenated solvent (chloroform, carbon tetrachloride, methylenechloride, dichloroethane) and washed with aqueous base (such as asolution of NaOH, KOH, NaHCO₃, Na₂ CO₃ or K₂ CO₃). The solution is driedover Na₂ SO₄ (or MgSO₄, CaCl₂, CaSO₄, K₂ CO₃, or other similar dryingagent) and the solvent is removed to give 2-B. In a third step,reduction of 2-B is effected by shaking with H₂ gas (1-3 atm) and Pd/C(5-10%) in an organic solvent such as ethanol, ethyl acetate, aceticacid or tetrahydrofuran until the theoretical amount of hydrogen isconsumed. The catalyst is removed by filtration and the solvent isevaporated to give 2-B'. Alternatively, 2-B is reduced in an etherealsolvent (ether, tetrahydrofuran, dioxane) with diborane followed bytreatment with a carboxylic acid at elevated temperature. Excess acid isneutralized and the solution is washed. The solution is dried over Na₂SO₄ (or MgSO₄, CaCl₂, CaSO₄, K₂ CO₃, or other similar drying agent),filtered, and solvent removed. In the final step, the urazole 2-B' ishydrolyzed with base such as NaOH, KOH or LiOH in an alcohol solventsuch as (methanol, ethanol, ethylene glycol, propylene glycol) atelevated temperatures. Air oxidation to the desired product 2-C occursspontaneously. The solution is diluted with water, washed with anorganic solvent such as ether or methylene chloride and dried over Na₂SO₄ (or other similar drying agent), filtered, and the solvent removed.Of course, it is clear that intermediate 2-C might have R^(5*)substituents at any of positions 4,5 and 6. ##STR11##

Referring to Scheme 3, intermediate 1-C or 2-C is converted to finalproduct in a one step acylation. In the arylation reaction,appropriately substituted 3-aryl-1,4,5,6-tetrahydropyddazine,intermediate 1-C or 2-C, is added with the appropriate acylating agent,i.e., phenyl carbonyl halide, phenyl sulphonyl halide or phenylphosphonyl dihalide, to an organic base such as pyridine or collidine,or to an organic solvent such as THF, methylene chloride or toluene witha base such as DMAP or triethylamine, or to an aqueous base such assodium or potassium hydroxide. ##STR12##

In the case of the reaction employing an phenylphosphonyl dihalide, analcohol such as methanol, ethanol, propanol, isopropanol, cyclopentanolor phenol is added after the reaction of the tetrahydropyridazine withthe phenylphosphonyl dihalide. The halide portion of the acylating agentmay be any reactive halide but preferred are chloro or bromo. Theproduct is isolated by pouring the reaction mixture into dilute acidsolution such as a hydrobromic or a hydrochloric acid solution andextracting with an organic solvent such as methylene chloride or ethylacetate. The organic layer is then concentrated, and the residuerecrystallized or chromatographed using for example methylene chlorideand/or ether and/or ethyl acetate and/or methanol on silica gel. Thefractions containing the product are evaporated and the residuerecrystallized from an appropriate solvent such as acetone, ether, ethylacetate, methanol, or hexane to afford the desired acylated compounds3-D to 3-G.

For example, to prepare the arylsulphonyltetrahydropyridazines 3-D, theappropriate phenylsulfonyl chloride is added at about room temperatureto a solution of the appropriate intermediate 1-C or 2-C in an organicsolvent such as pyridine or a solution of 4-N,N-dimethylaminopyridine inmethylene chloride, and the resulting mixture is stirred for about 1 toabout 72 hours. The reaction mixture is then treated with an acidicsolution such as dilute to 6N HCl or HBr, followed by successive washeswith an organic solvent such as chloroform or methylene chloride. Thecombined organic extracts are dried with a drying agent such as sodiumsulfate, magnesium sulfate or potassium carbonate, concentrated andchromatographed using for example methylene chloride and/or ether and/orethyl acetate and/or methanol on silica gel. The desired fractions arerecrystallized from a suitable organic solvent Such as ether, ethylacetate, methanol or hexane to yield the desiredphenylsulphonyltetrahydropyridazine 3-D.

Several general procedures are used for the preparation of thephenylcarbonyltetrahydropyridazines 3-E. For example, an appropriatephenylcarbonyl halide is added to a solution of the intermediate 1-C or2-C in an organic solvent such as dichloromethane or toluene. Theresulting mixture is heated to reflux for about 1 to about 4 hours,optionally stirred at about room temperature for about 16 hours, driedand concentrated. Column chromatography employing for example methylenechloride and/or ether and/or ethyl acetate and/or methanol on silica gelis then performed on the residue, followed by recrystallization of thedesired fractions from a suitable solvent such as ether, ethyl acetate,methanol or hexane to yield the desiredphenylcarbonyltetrahydropyridazine 3-E. In another example, anappropriate phenylcarbonyl is added to a solution of the appropriateintermediate 1-C or 2-C in an organic solvent such as collidine orpyridine. The resulting mixture is stirred at about room temperature forabout 1 to about 72 hours, dried and concentrated. The isolation of thephenylcarbonyltetrahydropyridazine 3-E is undertaken as notedpreviously. In yet another example, an appropriate phenylcarbonylchloride is added to a stirred solution of the intermediate 1-C or 2-Cin an organic solvent such as toluene or methylene chloride at aboutroom temperature under an dry atmospheric conditions such as argon orN₂. A tertiary amine such as dimethylaminopyridine or triethylamine isadded to the mixture and the progress of the reaction is monitored byTLC. The isolation of the phenylcarbonyltetrahydropyridazine 3-E whichis prepared under these conditions is undertaken as noted previously.The following general procedure is used for the preparation of thephenylphosphonyltetrahydropyridazines 3-F. For example anphenylphosphonyl dihalide such as 4-methoxyphenylphosphonic dichloride,4-chlorophenyl-phosphonic dichloride or phenylphosphonic dichloride isadded (preferably dropwise) to a solution of the appropriateintermediate 1-C or 2-C in an organic solvent such as collidine orpyridine at about 0° C. The reaction mixture is stirred at about 0° C.for about 1 hour, and then warmed to about room temperature. Anappropriate alcohol of the formula R₇ OH and including ethanol,methanol, propanol, butanol, cyclopentanol, isopropanol or phenol, isadded to the resulting mixture and this mixture stirred at about roomtemperature for about 16 hours. The work-up of the reaction mixture andthe isolation of the phenylphosphonyltetrahydropyridazine 3-F iseffected in the same manner as noted previously regarding thephenylsulphonyltetrahydropyridazines.

The appropriate acylating agents are well known to persons skilled inthe art and may be prepared as follows: benzenesulphonylhalide;(Beilstein 11, 34; phenylethenylsulphonyl halide, M. Culbertson, et al.,J. Chem. Soc. (C) 992, (1968) and Beilstein 11, 2;phenylmethylsulphonylhalide, Beilstein 11, 116; benzoylhalide, Beilstein9, 182; phenylacetylhalide, Beilstein 9, 436; cinnamoylhalide, Beilstein9, 587; and phenylphosphonyldihalide, Beilstein 16, 804.

Scheme 3 shows the following general procedure used for the preparationof the phenylthiocarbonyltetrahydropyridazines 3-H. For example, asulfurization agent such as Lawesons reagent or phosphorous pentasulfideis added to a solution of an appropriatephenylcarbonyltetrahydropyridazine 3-E in an inert organic solvent suchas benzene or toluene. The mixture is heated to reflux under dryatmospheric conditions such as argon or N₂ for about 2 hours, filteredand concentrated. The work-up of the reaction mixture and the isolationof the phenylthiocarbonyltetrahydropyridazines 3-H is effected in thesame manner as noted previously regarding thephenylcarbonyltetrahydropyridazines.

Referring to Scheme 4, compounds of the present invention in whichR^(5*) is a bivalent alkyl or alenyl radical attached at the 5- and6-position are favorably prepared via a cycloaddition between anappropriate azoalkene and an electron-rich alkene, e.g., dienes,including cyclopentadiene. The azoalkene is generated in situ by: (1)reacting the appropriate phenylsulphonylhydrazide with an appropriateα-bromo- or α-chloro-alkylarylketone, e.g., chloroacetophenone, to yieldthe corresponding hydrazone 4-A; and (2) treating the hydrazone 4-A witha base such as sodium hydroxide, potassium carbonate, sodium carbonateor sodium bicarbonate to produce final product 4-B. This reaction iffurther desribed by Clarke et al., J. Chem. Research (S), 310 (1985) andFaragher et al., J. Chem. Soc. Perkin Trans. I, 249 (1979). ##STR13##

For example, a 1-phenylsulphonyl hydrazide is added to a solution ofα-chloroacetophenone in an organic solvent such as THF or ether. Themixture is heated to reflux for about 2 hours and then concentrated.Upon cooling to about 0° C., a solid residue is produced. Theprecipitate is washed with an organic solvent such as ether or hexaneand dried to yield the corresponding hydrazone 4-A'. An electron-richdiene or alkene 4-A" (preferably freshly distilled) such as indene,1-methoxycyclohexene, dicyclopentadiene or cyclopentadiene in an organicsolvent such as ether or THF is added to a solution of the hydrazone,followed by the addition of a base such as potassium carbonate or sodiumbicarbonate. The mixture is stirred at about room temperature for about12 hours and then filtered through, for example, florisil or Celite. Thefiltrate is concentrated. The resulting residue is chilled to about 0°C. and triturated with an alcohol such as methanol or ethanol. A solidis precipitated out of the mixture, collected and washed with an organicsolvent such as ether or hexane to yield a compound of the invention4-B. Where the alkene employed is a diene, a product is produced thathas an unsaturated moiety, e.g., R^(5*) fused bi-radical such as --CH₂--CH═CH--. The compound having the unsaturated moiety may be treatedwith H₂ and a catalytic amount of a metal such as platinum oxide orpalladium on carbon in an alcohol such as isopropanol, methanol orethanol to yield the corresponding compound wherein the unsaturatedbi-radical is hydrogenated (saturated), i.e., the fused bi-radical --CH₂--CH═CH-- is converted to --(CH₂)₃ --. The reaction is effected byshaking a suspension of the compound having the unsaturated moiety in aParr Shaker apparatus under a H₂ atmosphere for about 1 to 3 hours, atabout 20 to 50 psi, filtering and concentrating. The resulting reductionproduct is purified by recrystallization from an organic solvent such asether, hexane, ethanol or ethyl acetate.

An alternate method by which an intermediate of the type of 1-C and 2-Cmay be made can be found in N. Kalyanam et al., SyntheticCommunications, 18 (16 and 17) (1988). In this method, an appropriateintermediate 1-C or 2-C is prepared directly from an appropriate4-halobutyl aryl ketone.

The invention also pertains to the racemate, individual stereoisomers,and mixtures thereof. The isomers are isolated by standard resolutiontechniques including fractional crystallization and chiral columnchromatography.

The compound of the present invention also include pharmaceuticallyacceptable salts and esters. Although the acylated tetrahydropyridzinesbase ring does not form salts or esters, substitutents thereon, whichinclude carboxy or amine groups may. In the case of salts, there areacid addition salts with amine containing substituents and base salts oralkali metal salts with carboxy containing substituents. Suitable acidaddition salts may be formed upon the combination of amine containingsubstituents with chlorides, such as hydrochloride; sulfates, such ashydrosulfate; acetates such as acetic acid; etc. Suitable base salts oralkali metal salts may be formed upon the combination of carboxycontaining substituents with nitrogen containing bases, such as,dimethylamine; alkali metal containing bases, such as sodium hydroxide,lithium hydroxide, or potassium carbonate. Persons skilled in the artare well familiar with these salts. In the case of esters, carboxycontaining substitutents may form desirable compounds as esters withmethyl, ethyl, propyl, butyl, etc.

Preferred species possessing progestin agonist activity are encompassedby the compounds selected from the group consisting of:3-(naphth-2-yl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-trifluoromethylbenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-chlorobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(2-naphthylenesulfonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-bromobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-methylbenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(4-chloro-3-trifluoromethylphenyl)-1-(4-trifluoromethylbenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(4-chloro-3-trifluoromethylphenyl)-1-(4-bromobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;(R,S)3-(3,4-dichlorophenyl)-1-(4-iodobenzenesulphonyl)-6-methyl-1,4,5,6-tetrahydropyridazineand (R,S)3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulphonyl)-6-methyl-1,4,5,6-tetrahydropyridazine.

Preferred species possessing progestin antagonist activity encompassedby the compounds selected from the group consisting of:

3-(3,4-dichlorophenyl)-1-(2,3-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(2,5-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(2-(3-carbomethoxypropxy)-5-bromobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(4-chloro-3-trifluoromethylphenyl)-1-(2,5-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydropyridazineand (R,S)3-(3,4-dichlorophenyl)-1-(2,5-dichlorobenzenesulphonyl)-5-methyl-1,4,5,6-tetrahydropyridazine.

Preferred species possessing bone growing activity encompassed by thecompounds selected from the group consisting of:

1-(3,4-dichlorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine;1-(3,4-dichlorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine;1-(3,4-difluorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine;1-(3-bromo-4-fluorothiobenzoyl)-3-phenyl-1,4,5,6-1tetrahydropyridazine;(R,S)-1-(3,4-difluorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine;(R,S)-1-(3,4-dichlorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine;(R,S)-1-(3,4-dichlorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine;(R,S)-1-(3,4-difluorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine

1-(3,4-dichlorobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine;1-(3,4-dichlorobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine;1-(3,4-dichlorothiobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazineand1-(3,4-dichlorothiobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine.

Certain compounds of the invention exhibit in vivo activity and they areuseful in treating biological disorders and conditions that aremodulated agonistically or antagonistically by steroids, e.g.,contraception, menopause, endometriosis, breast cancer, cycle synchrony,uterine fibroids, cervical dilation, osteoporosis and central nervoussystem conditions.

Pharmaceutical compositions that are used in treating the biologicaldisorders or conditions comprise the compounds of the invention as theactive ingredients in intimate admixture with a pharmaceutical carriercan be prepared according to conventional pharmaceutical compoundingtechniques. The carrier may take a wide variety of forms depending onthe form of preparation desired for administration, e.g., intravenous,oral, transdermal, intravaginal, suppository or parenteral. Thecomposition may also be administered by means of an aerosol. Inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like in the case of oral liquid preparations (such as,for example, suspensions, elixirs and solutions); or carriers such asstarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like in the case of oral solidpreparations (such as, for example, powders, capsules and tablets).Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe sugar-coated or enteric-coated by standard techniques. Forparenterals, the carrier will usually comprise sterile water, thoughother ingredients, for example, to aid solubility or for preservativepurposes, may be included, injectable suspensions may also be prepared,in which case appropriate liquid carriers, suspending agents and thelike may be employed. The pharmaceutical compositions will generally bein the form of a dosage unit, e.g., tablet, capsule, powder, injection,teaspoonful and the like, from about 1 μg/kg to about 100 mg/kg, andpreferably from about 20 μg/kg to about 20 mg/kg of the activeingredients.

Therefore, the compounds may be useful as contraceptives, and in thetreatment of menopause, endometriosis, breast cancer, cycle synchrony,uterine fibroids, cervical dilation and osteoporosis.

The following experimental examples describe the invention in greaterparticularity and are intended to be a way of illustrating but notlimiting the invention.

EXAMPLES 6-(4-Chlorophenyl)pyridazin-3-one

Hydrazine (8.9 mL, 0.28 mol) was added to a suspension of3-(4-chlorobenzoyl)propionic acid (30.0 g, 0.14 mol) in EtOH. Theresulting mixture was heated to reflux for 1 hour, stirred at roomtemperature overnight and chilled with an ice bath. The title compoundprecipitated out of this mixture (23.85 g, 81%) as a yellow solid: mp175°-176° C.

The following pyridazin-3-ones listed in Table 1 were preparedessentially by the above procedure, using the appropriate startingmaterials.

                  TABLE 1                                                         ______________________________________                                         ##STR14##                                                                    Cpd   R.sup.1          R.sup.5     mp                                         ______________________________________                                        1-1   4-Cl             H           175-176                                    1-2   3-Cl             H           148-150                                    1-3   4-Br             H           165-166                                    1-4   H                H           192-194                                    1-5   4-NMe.sub.2      H                                                      1-6   4-OMe            H           148-149                                    1-7   H                H           150-151                                    1-8   3-Cl, 4-Cl       H           168-169                                    1-9   3-CF.sub.3, 4-Cl H           191-192                                    1-10  4-n-Bu           H                                                      1-11  3-Br, 4-NH.sub.2 H                                                      1-12  3-Br, 5-Br       H                                                      1-13  3,4-(CH.sub.2).sub.4                                                                           H                                                      1-14  3,4-O(CH.sub.2).sub.2 O                                                                        H                                                      1-15  3,4-CHCHCHCH     H           209-210                                    1-16  2,3-CHCHCHCH     H           135-136                                    1-17  3,4-N(Me)C(O)CH.sub.2 S(O).sub.2                                                               H           300-301                                    1-18  3,4-N(Me)C(O)CH.sub.2 S                                                                        H           241-242                                    1-19  4-SCH.sub.3      H                                                      1-20  4-SO.sub.2 CH.sub.3                                                                            H                                                      1-21  H                5-CH.sub.3  155-158                                    1-22  H                5-CH.sub.3, 5-CH.sub.3                                                                    166-167                                    1-23  4-Ph             H           295-300                                    ______________________________________                                    

Example 2 (4-Chlorophenyl)pyridazine

A lithium aluminum hydride/THF solution (1 Molar, 173 mL) was addeddropwise to a suspension of pyridazin-3-one 1B (R₁ =4-Cl; 12.0 g, 57.5mmol) in THF at 0° C. The resulting mixture was heated to reflux for 1hour, and cooled to 0° C. Water (6.5 mL) was added to this mixture,followed by the successive addition of NaOH (1N, 6.5 mL), and of water(12 mL). The resulting precipitate was removed from the mother liquorfollowed by the treatment of said mother liquor with potassiumcarbonate. The resulting organic solution was concentratedarylphosphonyl dihalide to give the title compound as a thick oil (9.65g, 87%).

The following pyridazines listed in Table 2 were prepared essentially bythe above procedure, using the appropriate starting materials. All ofthe products are oils.

                  TABLE 2                                                         ______________________________________                                         ##STR15##                                                                    Cpd       R.sup.1           R.sup.5                                           ______________________________________                                        2-1       4-Cl              H                                                 2-2       3-Cl              H                                                 2-3       H                 H                                                 2-4       4-NHMe.sub.2      H                                                 2-5       4-OMe             H                                                 2-6       H                 H                                                 2-7       H                 5-CH.sub.3                                        2-8       H                 5-CH.sub.3, 5-CH.sub.3                            2-9       3-Cl, 4-Cl        H                                                 2-10      3-CF.sub.3, 4-Cl  H                                                 2-11      4-n-Bu            H                                                 2-12      3-Br, 4-NH.sub.2  H                                                 2-13      3-Br, 5-Br        H                                                 2-14      3,4-CHCHCHCH      H                                                 2-15      3,4-O(CH.sub.2).sub.2 O                                                                         H                                                 2-16      3,4-CHCHCHCH      H                                                 2-17      3,4-N(Me)C(O)CH.sub.2 S                                                                         H                                                 2-18      3,4-N(Me)C(O)CH.sub.2 S(O).sub.2                                                                H                                                 2-19      4-SCH.sub.3       H                                                 2-20      4-SO.sub.2 CH.sub.3                                                                             H                                                 2-21      4-Ph              H                                                 ______________________________________                                    

Example 33-(4-Chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(Compound 1)

4-iodobenzenesulfonyl chloride (1.18 g, 5.03 mmol) was added at roomtemperature to a solution of pyridazine (1C) (R₁ =3-CF₃, 4-Cl: 0.62 g,2.36 mmol) in pyridine and the resulting mixture was stirred for 16 h.2N HCl was added to the reaction mixture followed by successive washeswith methylene chloride. The combined organic extracts were dried (K₂CO₃), concentrated arylphosphonyl dihalide and passed through a columnof silica gel. The desired fractions were recrystallized from ethylacetate/ether to give the title compound as a solid (0.30 g): mp153°-154° C.

Anal. Calc'd for C₁₇ H₁₃ ClF₃ IN₂ O₂ S: C, 38.61; H, 2.48; N, 5.30Found: C, 38.81; H, 2.44; N, 5.32

The following acylated pyridazines listed in Table 3, Table 3a and Table4 were prepared essentially by the above procedure, using theappropriate starting materials.

                                      TABLE 3                                     __________________________________________________________________________     ##STR16##                                                                                                        Analysis                                  Cpd                                                                              R.sup.1       R.sup.3       mp:(°C.)                                                                    C  H  N                                   __________________________________________________________________________     1 3-CF.sub.3, 4-Cl                                                                            4-I           153-154                                                                            38.81                                                                            2.44                                                                             5.32                                 2 H             4-Me          160-161                                                                            65.00                                                                            5.72                                                                             9.05                                 3 4-OMe         4-Me          141-142                                                                            62.50                                                                            5.69                                                                             8.13                                 4 4-Cl          4-NO.sub.2    164-165                                                                            50.73                                                                            3.58                                                                             11.15                                5 4-Cl          2-Cl, 5-Cl    148-149                                                                            47.67                                                                            3.16                                                                             6.91                                 6 4-Cl          4-Cl          170-171                                                                            52.14                                                                            3.68                                                                             7.52                                 7 4-F           4-Cl          151-152                                                                            54.31                                                                            3.84                                                                             8.08                                 8 4-Cl          4-Me          157-158                                                                            58.57                                                                            4.86                                                                             8.01                                 9 4-F           4-Me          139-140                                                                            61.42                                                                            4.96                                                                             8.45                                10 4-F           4-NO.sub.2    152-153                                                                            52.78                                                                            3.69                                                                             11.34                               11 4-F           2-Cl, 5-Cl    122-123                                                                            49.50                                                                            3.14                                                                             7.16                                12 4-Cl, 3-Cl    4-Cl          153-154                                                                            48.61                                                                            3.23                                                                             7.16                                13 4-Cl          4-Br          178-180                                                                            46.50                                                                            3.18                                                                             6.56                                14 4-Cl          3-NO.sub.2    162-163                                                                            50.66                                                                            3.51                                                                             10.86                               15 4-Cl          2,3-CHCHCHCH  148-149                                                                            62.62                                                                            4.07                                                                             7.27                                16 4-Cl          4-I           162-163                                                                            41.93                                                                            2.80                                                                             5.98                                17 4-Cl          4-F           159-160                                                                            54.57                                                                            3.77                                                                             8.07                                18 4-F           4-F           147-148                                                                            57.18                                                                            3.87                                                                             8.55                                19 4-F           4-Br          157-158                                                                            48.34                                                                            3.23                                                                             6.87                                20 4-F           4-I           150-151                                                                            43.27                                                                            2.90                                                                             6.04                                21 4-F           4-F, 3-NO.sub.2                                                                             149-150                                                                            52.88                                                                            3.60                                                                             11.37                               22 4-Cl, 3-Cl    2-Cl, 5-Cl    176-177                                                                            43.88                                                                            2.68                                                                             6.22                                23 4-F           2-NO.sub.2, 4-NO.sub.2                                                                      149-150                                                                            46.85                                                                            3.11                                                                             13.71                               24 4-F           2-NO.sub.2    159-160                                                                            52.48                                                                            3.76                                                                             11.44                               25 4-F           3,4-CHCHCHCH  179-180                                                                            65.14                                                                            4.63                                                                             7.64                                26 4-F           2-CO.sub.2 Me 150-151                                                                            57.22                                                                            4.51                                                                             7.40                                27 4-Cl          2-NO.sub.2    182-183                                                                            50.68                                                                            3.74                                                                             11.34                               28 4-Cl          2-NO.sub.2, 4-NO.sub.2                                                                      186-187                                                                            45.22                                                                            2.97                                                                             13.20                               29 4-Cl          2-CO.sub.2 Me 153-154                                                                            55.15                                                                            4.22                                                                             7.12                                30 4-Cl          3-Cl, 4-Cl    163-164                                                                            47.63                                                                            3.18                                                                             7.08                                31 4-Cl          3-Cl, 5-Cl    149-150                                                                            47.70                                                                            3.14                                                                             6.93                                32 4-Cl          2-F, 4-F      115-116                                                                            52.11                                                                            3.46                                                                             7.51                                33 4-Cl          3-CF.sub.3, 5-CF.sub.3                                                                      154-155                                                                            45.99                                                                            2.66                                                                             5.75                                34 4-Cl          3-NO.sub.2    187-188                                                                            46.24                                                                            3.12                                                                             10.10                               35 4-Cl          3-CF.sub.3    178-179                                                                            50.76                                                                            3.47                                                                             6.93                                36 4-Cl          4-CF.sub.3    126-127                                                                            50.97                                                                            3.38                                                                             6.90                                37 4-Cl          H             203-204                                                                            57.38                                                                            4.37                                                                             8.35                                38 4-Cl, 3-Cl    4-NO.sub.2    174-175                                                                            46.54                                                                            3.14                                                                             10.18                               39 4-Cl, 3-Cl    4-Br          175-176                                                                            42.42                                                                            2.99                                                                             6.43                                40 4-Cl, 3-Cl    4-I           184-185                                                                            39.24                                                                            2.67                                                                             5.76                                41 4-Cl, 3-Cl    4-Me          150-151                                                                            53.65                                                                            4.17                                                                             7.29                                42 4-Cl, 3-Cl    3,4-CHCHCHCH  136-137                                                                            57.49                                                                            3.79                                                                             6.74                                43 4-Cl, 3-Cl    H             160-161                                                                            52.00                                                                            3.88                                                                             7.75                                44 4-Cl          2,3-CHCHCHCH  195-196                                                                            62.35                                                                            4.39                                                                             7.30                                45 4-Cl, 3-Cl    4-n-Bu        140-141                                                                            61.39                                                                            5.90                                                                             7.21                                46 4-Cl, 3-Cl    3,4-C(NMe.sub.2)CHCHCH                                                                      164-165                                                                            61.80                                                                            5.36                                                                             9.89                                47 4-Cl, 3-Cl    2-CO.sub.2 Me 121-122                                                                            50.63                                                                            3.75                                                                             6.49                                48 H             4-Cl          153-154                                                                            57.24                                                                            4.34                                                                             8.66                                49 H             4-Br          145-146                                                                            50.65                                                                            3.64                                                                             7.68                                50 H             4-I           143-144                                                                            44.99                                                                            3.15                                                                             6.70                                51 H             3,4-CHCHCHCH  137-138                                                                            68.37                                                                            5.19                                                                             8.28                                52 H             2-Cl, 5-Cl    140-141                                                                            51.93                                                                            3.59                                                                             7.16                                53 H             4-NO.sub.2    170-171                                                                            55.88                                                                            3.97                                                                             11.77                               54 H             4-F           125-126                                                                            60.54                                                                            4.45                                                                             8.39                                55 H             4-n-Bu        84-85                                                                              67.34                                                                            6.46                                                                             7.52                                56 H             2,3-CHCHCHCH  177-178                                                                            68.23                                                                            5.10                                                                             7.91                                57 H             3,4-C(NMe.sub.2)CHCHCH                                                                      139-140                                                                            67.04                                                                            5.66                                                                             10.39                               58 H             4-Cl, 3-NO.sub.2                                                                            127-128                                                                            50.50                                                                            3.45                                                                             10.98                               59 H             2-F, 4-F      120-121                                                                            56.97                                                                            3.84                                                                             8.30                                60 H             3-Cl, 4-Cl    140-141                                                                            51.99                                                                            3.54                                                                             7.55                                61 H             4-CF.sub.3    155-156                                                                            55.77                                                                            3.94                                                                             7.67                                62 H             3-NO.sub.2    173-174                                                                            55.61                                                                            3.99                                                                             11.90                               63 4-OMe         4-Cl          164-165                                                                            56.11                                                                            4.47                                                                             7.61                                64 4-OMe         H             185-186                                                                            61.85                                                                            5.22                                                                             8.45                                65 4-OMe         3,4-CHCHCHCH  145-147                                                                            66.28                                                                            5.22                                                                             7.40                                66 H             H             167-168                                                                            64.04                                                                            5.29                                                                             9.32                                67 4-Cl          4-Cl, 4-NO.sub.2                                                                            186-187                                                                            46.51                                                                            3.31                                                                             10.22                               69 4-n-Bu        2-Cl, 5-Cl    95-97                                                                              56.41                                                                            5.22                                                                             6.59                                70 4-n-Bu        3-NO.sub.2    119-120                                                                            59.91                                                                            5.61                                                                             10.31                               71 4-n-Bu        4-I           121-122                                                                            49.65                                                                            4.69                                                                             5.63                                72 4-n-Bu        3,4-CHCHCHCH  140-141                                                                            70.87                                                                            6.33                                                                             6.74                                73 4-n-Bu        4-Cl          108-109                                                                            61.32                                                                            5.74                                                                             7.04                                74 4-n-Bu        4-Me          106-107                                                                            68.10                                                                            7.01                                                                             7.58                                75 4-n-Bu        4-n-Bu        102-103                                                                            69.66                                                                            7.79                                                                             6.83                                76 4-n-Bu        H             109-110                                                                            67.24                                                                            6.71                                                                             7.93                                77 3-CF.sub.3, 4-Cl                                                                            4-Cl          134-135                                                                            46.78                                                                            2.91                                                                             6.47                                78 3-CF.sub.3, 4-Cl                                                                            3,4-(CH.sub.2).sub.4 -                                                                      130-131                                                                            38.81                                                                            2.44                                                                             5.32                                79 3-CF.sub.3, 4-Cl                                                                            2-Cl, 5-Cl    160-161                                                                            55.56                                                                            3.44                                                                             6.26                                80 3-CF.sub.3, 4-Cl                                                                            3-Cl, 5-Cl    124-125                                                                            43.42                                                                            2.54                                                                             6.02                                81 3-CF.sub.3, 4-Cl                                                                            3-Cl, 4-Cl    138-139                                                                            43.27                                                                            2.52                                                                             5.87                                82 3-CF.sub.3, 4-Cl                                                                            4-Me          136-137                                                                            43.77                                                                            2.55                                                                             6.10                                83 3-CF.sub.3, 4-Cl                                                                            H             155-156                                                                            52.21                                                                            3.73                                                                             6.80                                84 4-Ph          4-Cl          194-195                                                                            64.08                                                                            4.62                                                                             6.78                                85 4-Ph          3,4-CHCHCHCH  193-194                                                                            73.28                                                                            5.07                                                                             6.52                                86 4-Ph          H             204-205                                                                            69.92                                                                            5.34                                                                             7.42                                87 3,4-(CH.sub.2).sub.4 -                                                                      4-Me          143-144                                                                            68.43                                                                            6.81                                                                             7.46                                88 3,4-(CH.sub.2).sub.4 -                                                                      4-Cl          165-166                                                                            61.72                                                                            5.57                                                                             7.11                                89 3,4-(CH.sub.2).sub.4 -                                                                      2-Cl, 5-Cl    153-153                                                                            56.75                                                                            4.60                                                                             6.56                                90 3,4-(CH.sub.2).sub.4 -                                                                      H             151-153                                                                            67.52                                                                            6.37                                                                             7.91                                91 3-Cl          2-Cl, 5-Cl    115-116                                                                            47.64                                                                            3.01                                                                             6.82                                92 3-Cl          4-Me          129-130                                                                            58.53                                                                            4.91                                                                             8.07                                93 3-Cl          4-Cl          123-124                                                                            51.95                                                                            3.66                                                                             7.53                                94 3-Cl          3,4-CHCHCHCH  154-155                                                                            51.95                                                                            3.66                                                                             7.53                                95 3-Cl          H             129-130                                                                            57.22                                                                            4.37                                                                             8.36                                96 3-Cl          4-I           131-132                                                                            41.75                                                                            2.98                                                                             6.04                                97 4-Cl, 3-Cl    4-CF.sub.3    139-141                                                                            46.48                                                                            2.92                                                                             6.46                                98 4-Cl, 3-Cl    3-CF.sub.3    185-186                                                                            46.64                                                                            2.76                                                                             6.18                                99 4-Br          4-Cl          182-183                                                                            46.13                                                                            3.18                                                                             6.38                                100                                                                              4-Br          4-Br          192-193                                                                            41.80                                                                            2.96                                                                             5.73                                101                                                                              4-Br          4-Me          175-176                                                                            51.94                                                                            4.29                                                                             6.90                                102                                                                              4-Br          2-Cl, 5-Cl    168-169                                                                            42.56                                                                            2.86                                                                             5.99                                103                                                                              4-Br          H             205-206                                                                            50.59                                                                            3.92                                                                             7.09                                104                                                                              4-Cl, 3-Cl    3-Cl, 5-Cl    142-143                                                                            43.76                                                                            2.59                                                                             6.10                                105                                                                              4-Cl, 3-Cl    2-Cl, 3-Cl    142-144                                                                            43.81                                                                            2.66                                                                             6.25                                106                                                                              4-Cl, 3-Cl    4-F           141-142                                                                            49.52                                                                            3.30                                                                             7.03                                108                                                                              4-Cl, 3-Cl    4-n-Bu        128-129                                                                            56.43                                                                            5.18                                                                             6.28                                109                                                                              4-Cl, 3-Cl    3-Cl          189-190                                                                            47.49                                                                            3.23                                                                             6.62                                110                                                                              4-Cl, 3-Cl    2,3-CHCHCHCH  150-151                                                                            57.16                                                                            3.81                                                                             6.46                                111                                                                              4-Cl, 3-Cl    3-NO.sub.2, 4-Cl                                                                            157-158                                                                            42.93                                                                            2.60                                                                             8.98                                112                                                                              3,4-C(OMe)HCHCHCH                                                                           4-I           143-145                                                                            50.19                                                                            3.68                                                                             5.37                                113                                                                              3,4-(CH.sub.2).sub.4 -                                                                      4-I           170-172                                                                            50.03                                                                            4.47                                                                             5.86                                114                                                                              4-Cl, 3-Cl    3,4-(CH.sub.2).sub.4 -                                                                      135-136                                                                            56.59                                                                            4.53                                                                             6.55                                115                                                                              3-CF.sub.3, 4-Cl                                                                            4-Br          139-140                                                                            42.45                                                                            2.70                                                                             5.82                                116                                                                              3-CF.sub.3, 4-Cl                                                                            4-n-Bu        95-96                                                                              54.97                                                                            4.79                                                                             6.04                                117                                                                              3,4-CHCHCHCH  4-Cl          160-161                                                                            62.38                                                                            4.30                                                                             7.24                                118                                                                              3,4-CHCHCHCH  2-Cl, 5-Cl    158-159                                                                            57.26                                                                            3.72                                                                             6.69                                119                                                                              3,4-CHCHCHCH  4-I           169-170                                                                            50.27                                                                            3.48                                                                             5.67                                120                                                                              3,4-CHCHCHCH  4-Me          153-154                                                                            69.27                                                                            5.26                                                                             7.73                                121                                                                              4-Cl, 3-Cl    4-n-Hex       96-97                                                                              58.17                                                                            5.63                                                                             6.10                                122                                                                              2,3-CHCHCHCH  4-Me          159-163                                                                            61.99                                                                            4.25                                                                             7.09                                123                                                                              3,4-O(CH.sub.2).sub.2 O-                                                                    2-Cl, 5-Cl    147-148                                                                            50.61                                                                            3.53                                                                             6.56                                124                                                                              3,4-O(CH.sub.2).sub.2 O-                                                                    4-Cl          143-145                                                                            55.21                                                                            4.04                                                                             7.17                                125                                                                              3-CF.sub.3, 4-Cl                                                                            4-CF.sub.3    104-106                                                                            46.30                                                                            2.54                                                                             2.65                                126                                                                              3-CF.sub.3, 4-Cl                                                                            3-CF.sub.3    144-145                                                                            45.88                                                                            2.72                                                                             5.84                                127                                                                              3-CF.sub.3, 4-Cl                                                                            3-NO.sub.2    149-150                                                                            45.58                                                                            2.82                                                                             9.19                                128                                                                              3-CF.sub.3, 4-Cl                                                                            4-NO.sub.2    172-173                                                                            45.66                                                                            2.81                                                                             8.98                                129                                                                              3,4-CHCHCHCH  4-CF.sub.3    166-167                                                                            60.08                                                                            3.74                                                                             6.67                                130                                                                              3,4-CHCHCHCH  3-CF.sub.3    154-155                                                                            60.14                                                                            3.79                                                                             6.66                                131                                                                              3,4-CHCHCHCH  H             198-200                                                                            68.39                                                                            5.01                                                                             8.00                                132                                                                              3,4-CHCHCHCH  3,4-CHCHCHCH  173-174                                                                            71.63                                                                            4.67                                                                             6.91                                133                                                                              H             4-OCH.sub.3   115-117                                                                            61.89                                                                            5.41                                                                             8.15                                134                                                                              4-SCH.sub.3   4-CH.sub.3    159-161                                                                            60.02                                                                            5.56                                                                             7.74                                135                                                                              4-SCH.sub.3   4-I           177-179                                                                            43.39                                                                            3.57                                                                             5.84                                136                                                                              4-Cl, 3-Cl    2-O(CH.sub.2).sub.3 CO.sub.2 Me, 5-Br                                                       76-79                                                                              45.66                                                                            4.06                                                                             4.61                                137                                                                              4-OMe         2-O(CH.sub.2).sub.3 CO.sub.2 Me, 5-Br                                                       96-97                                                                              51.20                                                                            5.01                                                                             5.12                                138                                                                              3,4-N(Me)C(O)CH.sub.2 S                                                                     4-I           199-203                                                                            43.62                                                                            3.09                                                                             7.65                                139                                                                              3,4-N(Me)C(O)CH.sub.2 S                                                                     4-I           127-131                                                                            39.97                                                                            3.01                                                                             7.02                                140                                                                              H             4-SCH.sub.3   120-121                                                                            58.89                                                                            5.26                                                                             7.99                                __________________________________________________________________________

                  TABLE 3a                                                        ______________________________________                                         ##STR17##                                                                                         Analysis                                                 Cpd  R.sup.1  R.sup.3  R.sup.a                                                                            mp:(°C.)                                                                      C    H     N                               ______________________________________                                         68  4-Cl     2-Cl, 4-Cl                                                                             5-Cl 151-152                                                                              43.87                                                                              2.83  6.42                            107  4-Cl, 3-Cl                                                                             2-Cl, 4-Cl                                                                             5-Cl 184-185                                                                              40.60                                                                              2.34  5.85                            ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                         ##STR18##                                                                                         Analysis                                                 Cpd.  R.sup.1 R.sup.3  R.sup.5                                                                            mp:(°C.)                                                                      C    H     N                               ______________________________________                                        141   H       3-CF.sub.3                                                                             5-Me 30-131 56.37                                                                              4.14  7.32                            142   H       4-Br     5-Me 34-135 52.00                                                                              4.26  7.11                            143   H       4-Me     5-Me 38-139 65.55                                                                              6.24  8.48                            144   H       2-Cl, 5-Cl                                                                             5-Me 54-155 53.25                                                                              4.00  7.24                            ______________________________________                                    

Example 43-(Dibenzofuran-3-yl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyradazine(Compound 145)

4-Iodobenzenesulfonyl chloride (0.54 g, 2.16 mmol) was added at roomtemperature to a solution of 4-oxo-4-(dibenzofuran-4-yl)butyric acid(0.65 g, 2.16 mmol) in pyridine and the resulting mixture was stirredfor 16 hours. 2N HCl was added to the reaction mixture followed bysuccessive washes with methylene chloride. The combined organic extractswere dried (K₂ CO₃), concentrated arylphosphonyl dihalide and passedthrough a column of silica gel. The desired fractions wererecrystallized from ethyl acetate/ether/hexane to give the titlecompound as a solid (0.14 g): mp 166°-169° C.

Anal. Calc'd for C₂₂ H₁₇ IN₂ O₃ S: C, 51.17; H, 3.32; N, 5.43 Found: C,51.27; H, 3.30; N, 5.23

Example 51-(4-Methylbenzoyl)-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine(Compound 146)

The title compound was prepared as described in Example 4 starting with4-oxo-4-(dibenzofuran-4-yl)butyric acid (0.54 g, 2.16 mmol) and4-chlorobenzenesulfonyl chloride (0.46 mL, 2.16 mmol) to give a solid:mp 163°-166° C.

Anal. Calc'd for C₂₂ H₁₇ ClN₂ O₃ S: C, 69.10; H, 5.49; N, 8.95 Found: C,69.31; H, 5.35; N, 9.02

Example 61-(4-Methylsulfinylbenzenesulfonyl)-3-phenyl-1,4,5,6-tetrahydropyridazine(Compound 1471)

MCPBA (0.63 g) was added at room temperature to a solution of3-phenyl-1-(4-thiomethylbenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(1.0 g) in methylene chloride. The resulting mixture was stirred andmonitored by TLC until the starting pyridazine was exhausted. Themixture was concentrated arylphosphonyl dihalide and purified by columnchromatography on silica gel using methylene chloride as an eluent togive a solid: mp 137°-139° C.

Anal. Calc'd for C₁₇ H₁₈ N₂ O₃ S2: C, 56.33; H, 5.00; N, 7.73 Found: C,56.37; H, 4.87; N, 7.54

Example 71-(4-Iodobenzenesulfonyl)-3-(4-methylsulfinylphenyl)-1,4,5,6-tetrahydropyridazine(Compound 148)

A solution of1-(4Iodobenzenesulfonyl)-3-(4-methylthiophenyl)-1,4,5,6-tetrahydropyridazine(1.27 g, 2.69 mmol) in methanol (450 mL) was added to a solution ofsodium periodate (0.61 g, 2.82 mmol) in water (6 mL) and stirred at alow heat for 16 hours. The resulting mixture was filtered, concentratedarylphosphonyl dihalide and purified by column chromatography on silicagel using ether/methylene chloride as an eluent to give the titlecompound as a solid: mp 191°-193° C.

Anal. Calc'd for C₁₇ H₁₇ IN₂ O₃ S₂ : C, 41.81; H, 3.52; N, 5.73 Found:C, 42.21; H, 3.77; N, 5.46

Example 81-(4-Methylnenzenesulfonyl)-3-(4-methylsulfinylphenyl)-1,4,5,6-tetrahydropyridazine(Compound 149)

The title compound was prepared as described in Example 7 starting with1,4,5,6-tetrahydro-1-(4-methylbenzenesulfonyl)-3-(4-methylthiophenyl)pyridazine(1.0 g, 2.77 mmol) and sodium periodate (0.62 g, 2.91 mmol) in water(5.82 mL) to give a solid: mp 212°-213° C.

Anal. Calc'd for C₁₈ H₂₀ N₂ O₃ S₂ : C, 57.42; H, 5.37; N, 7.44 Found: C,57.32; H, 5.45; N, 7.52

Example 91-(Methylbenzenesulfonyl)-3-(4-methylsulfonylphenyl)-1,4,5,6-tetrahydropyridazine(Compound 150)

The title compound was prepared as described in Example 6 staring with1-(4-methylbenzenesulfonyl)-3-(4-methylsulfinylphenyl)-1,4,5,6-tetrahydropyridazine(0.5 g, 1.33 mmol) and MCPBA (0.28 g, 1.33 mmol) to give a solid: mp229°-230° C.

Anal. Calc'd for C₁₈ H₂₀ N₂ O₄ S₂ : C, 55.08; H, 5.15; N, 7.13 Found: C,54.73; H, 5.28; N, 6.82

Example 101-(4-Iodobenzenesulfonyl)-3-(4-methylsulfonylphenyl)-1,4,5,6-tetrahydropyridazine(Compound 151)

The title compound was prepared as described in Example 6 staring with1-(4-iodobenzenesulfonyl)-3-(4-methylsulfinylphenyl)-1,4,5,6-tetrahyclropyridazine(0.5 g, 1.02 mmol) and MCPBA (0.22 g, 1.02 mmol) to give a solid: mp198°-204° C.

Anal. Calc'd for C₁₈ H₂₀ IN₂ O₄ S₂ : C, 40.48; H, 3.40; N, 5.55 Found:C, 40.45; H, 3.07; N, 5.44

Example 113-(4-Fluorophenyl)-1-(pentafluorobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(Compound 152)

The title compound was prepared as described in Example 3 starting withpyridazine (1C) (R₁ =4-F) and pentafluorobenzenesulfonyl chloride togive a solid: mp 140°-141° C.

Anal. Calc'd for C₁₆ H₁₀ F₆ N₂ O₂ S: C, 47.06; H, 2.47; N, 686 Found: C,47.14; H, 2.32; N, 6.85

Example 121-(4-Aminobenzenesulfonyl)-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine(Compound 153)

(4-Chlorophenyl)-1-(4-nitrobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(2.12 g, 5.60 mmol) was suspended in acetic acid at 80° C. Iron filings(3.0 g) were added to this suspension and the resulting reaction mixturewas heated at 80° C. for 30 minutes and filtered. Upon cooling the titlecompound precipitated out of this mixture as a solid: mp 205°-206° C.

Anal. Calc'd for C₁₆ H₁₆ ClN₃ O₂ S: C, 54.92; H, 4.61; N, 12.01 Found:C, 54.92; H, 4.64; N, 12.17

Example 131-(4-Aminoacetylbenzenesulfonyl)-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine(Compound 154)

(4-Aminobenzenesulfonyl)-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine(0.52 g) was dissolved in acetic anhydride and stirred at roomtemperature for 1.5 hours. Upon cooling the title compound precipitatedout of this mixture as a solid: mp 247°-248° C.

Anal. Calc'd for C₁₈ H₁₈ ClN₃ O₃ S: C, 55.16; H, 4.64; N, 10.72 Found:C, 55.34; H, 4.60; N, 10.74

Example 14 3-Phenyl-1-(4-methylbenzenesulfonyl)-4,4a,5,7a-tetrahydro-1H-cyclopenta c!pyridazine (Compound 155)

4-Toluenesulfonylhydrazide (5 g) was added to a solution ofalphachloroacetophenone (4.55 g) in ether. The mixture was heated atreflux for 2 hours and concentrated arylphosphonyl dihalide. Cooling theresulting residue to 0° C. produced a solid precipitate which was washedwith hexane and dried to give the hydrazone (4A') (X=Cl, H₁ =H, R₃=4-CH₃ ; 5.3 g) as a solid:

Freshly distilled cyclopentadiene (3 mL) was added to a solution ofhydrazone (4A') (X=Cl, H₁ =H, R₃ =4-CH₃ ; 1.5 g) in THF, followed by theaddition of sodium bicarbonate (2.5 g). The mixture was stirred at 22°C. for 12 hours and filtered through celite. The filtrate wasconcentrated arylphosphonyl dihalide, and the resulting residue waschilled with ice and triturated with ethanol. A solid precipitated outof this mixture which was collected and washed with hexane to give thetitle compound as a solid: mp 163°-165° C.

Anal. Calc'd for C₂₀ H₂₀ N₂ O₂ S: C, 68.15; H, 5.73; N, 7.94 Found: C,67.97; H, 5.94; N, 8.26

Example 154,4a,5,6,7,7a-Hexahydro-3-phenyl-1-(4-methylbenzenesulfonyl)-1H-cyclopentac!pyridazine(Compound 156)

A catalytic amount of palladium on carbon was added to a solution of3-phenyl-1-(4-tolylsulfonyl)-4,4a,5,7a-tetrahydro-1H-cyclopentac!pyridazine (0.5 g) in ethanol. The suspension was placed in a ParrShaker apparatus under a H₂ atmosphere (40 PSI) and shaken for 3 hours.The mixture was filtered through celite and concentrated. The resultingresidue was purified by recrystallization from ethyl acetate to give thetitle compound as a solid: mp 171°-176° C.

Anal. Calc'd for C₂₀ H₂₂ N₂ O₂ S: C, 67.76; H, 6.27; N, 7.90 Found: C,67.63; H, 6.38; N, 7.99

Example 161,4,4a,9a-Tetrahydro-1-(4-methylbenzenesulfonyl)-3-phenyl-bicyclo2.2.1!hept-7-enyl 5.6-a!cyclopenta- 1.2-e!pyridazine (Compound 157)

The title compound was prepared as described in Example 14 usingdicyclopentadiene (5.5 mL) in place of cyclopentadiene to give a solid:mp 155°-159° C.

Anal. Calc'd for C₂₅ H₂₆ N₂ O₂ S: C, 71.73; H, 6.27; N, 6.69 Found: C,71.75; H, 6.32N, 6.60

Example 171,4,4a,9a,-Tetrahydro-4-(4-methylbenzenesulfonyl)-2-phenyl-3,4-diazafluoreneHemihydrate (Compound 158)

The title compound was prepared as described in Example 14 using indene(3.45 mL) in place of cyclopentadiene to give a solid: mp 180°-181° C.

Anal. Calc'd for C₂₄ H₂₂ N₂ O₂ S: C, 70.04; H, 5.40; N, 6.80 Found: C,70.05; H, 5.56; N, 6.93

Example 181,4,4a,5,6,7,8,8a-Octahydro-8a-methoxy-1-(4-methyl-benzenesulfonyl)-3-phenyl-1,2-diazanapthalene(Compound 159)

The title compound was prepared as described in Example 14 using1-methoxycyclohexene (2.7 g) in place of cyclopentadiene to give asolid: mp 112°-114° C.

Anal. Calc'd for C₂₂ H₂₆ N₂ O₃ S: C, 66.30; H, 6.60; N, 7.03 Found: C,66.07; H, 6.34; N, 6.94

Example 193-(4-Chlorophenyl)-1-(4-iodobenzenesulfonyl)-4,4a,5,7a-tetrahydro-1H-cyclopentac!pyridiazine (Compound 160)

The title compound was prepared as described in Example 14 starting with4-iodobenzenesulfonyl hydrazide (2 g), 2-bromo-4'-chloroacetophenone(1.57 g) and cyclopentadiene to give a solid: mp 198°-201° C.

Anal. Calc'd for C₁₉ H₁₆ ClIN₂ O₂ S: C, 45.75; H, 3.24; N, 5.61 Found:C, 45.72; H, 3.05; N, 5.46

Example 201,4,4a,9a-Tetrahydro-1-(4-methylbenzenesulfonyl)-3-(3bromophenyl)bicyclo2.2.1!hept-7-enyl 5.6-a!cyclopenta 1.2-e!pyridazine (Compound 161)

The title compound was prepared as described in Example 14 starting with4-toluenesulfonyl hydrazide (8.8 g), 2-bromo-3'-bromoacetophenone (13.17g) and dicyclopentadiene (8.8 mL) to give a solid: mp 159°-161° C.

Anal. Calc'd for C₂₅ H₂₅ BrN₂ O₂ S: C, 60.36; H, 5.08; N, 5.63 Found: C,60.45; H, 4.95; N, 5.46

Example 214,4-Dibromo-3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(Compound 162)

Bromine (5 g) in acetic acid (5 mL) was added to a solution of3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(1.0 g) in acetic acid (50 mL). The mixture was stirred at 25° C. for 3hours and concentrated arylphosphonyl dihalide. The residue wasrecrystallized from ether to give the title compound as a solid: mp148°-150° C.

Anal. Calc'd for C₁₇ H₁₁ Br₂ ClF₃ IN₂ O₂ : C, 29.74; H, 1.62; N, 4.08Found: C, 30.02; H, 1.63; N, 4.00

Example 222-(3-Chlorophenylethene)sulfonyl!-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine(Compound 163)

3-Chlorostyrenesulfonyl chloride (1.07 g, 4.5 mmol) was added at roomtemperature to a solution of pyridazine (1C) (R₁ =4-Cl, 3-Cl: 0.88 g,4.5 mmol) in pyridine and the resulting mixture was stirred for 16hours. 2N HCl was added to the reaction mixture followed by successivewashes with methylene chloride. The combined organic extracts were dried(K₂ CO₃), concentrated arylphosphonyl dihalide and purified by columnchromatography on silica gel. The desired fractions were recrystallizedfrom ethyl acetate/ether to give the title compound as a solid:(0.33 g):mp 142°-143° C.

Anal. Calc'd for C₁₈ H₁₆ Cl₂ N₂ O₂ S: C, 54.67; H, 4.09; N, 7.08 Found:C, 54.67; H, 4.09; N, 7.08

The following acylated pyridazines listed in Table 5 were preparedessentially by the above procedure, using the appropriate startingmaterials. The substituted styrene sulfonylchlorides used to prepare thedesired compounds were synthesized using the procedure described inCulbertson, M. et al., J. Chem. Soc.(C) 992 (1968).

                                      TABLE 5                                     __________________________________________________________________________     ##STR19##                                                                                                    Analysis                                      Cpd.                                                                             R.sup.1     R.sup.3     mp:(°C.)                                                                    C  H  N                                       __________________________________________________________________________    164                                                                              4-Cl        3,4-CHCHCHCH                                                                              167-168                                                                            64.36                                                                            4.67                                                                             6.83                                    165                                                                              4-Cl        4-Cl        161-162                                                                            54.59                                                                            3.93                                                                             7.13                                    166                                                                              4-Cl        H           148-149                                                                            60.90                                                                            4.84                                                                             7.49                                    167                                                                              4-Cl, 3-Cl  H           139-140                                                                            54.75                                                                            4.04                                                                             7.05                                    168                                                                              4-Cl, 3-Cl  Ph          171-172                                                                            61.34                                                                            4.02                                                                             5.78                                    169                                                                              4-Cl, 3-Cl  4-Me        138-139                                                                            55.79                                                                            4,44                                                                             6.75                                    170                                                                              4-Cl, 3-Cl  4-Cl        157-158                                                                            50.23                                                                            3.54                                                                             6.44                                    171                                                                              4-Cl, 3-Cl  3,4-CHCHCHCH                                                                              209-210                                                                            59.48                                                                            3.97                                                                             6.30                                    172                                                                              4-Cl, 3-Cl  3-Cl        131-132                                                                            50.33                                                                            3.35                                                                             6.52                                    173                                                                              4-Cl, 3-Cl  2-Cl        154-155                                                                            50.16                                                                            3.30                                                                             6.52                                    174                                                                              3,4-CHCHCHCH                                                                              H           158-159                                                                            70.26                                                                            5.01                                                                             7.33                                    175                                                                              3,4-CHCHCHCH                                                                              4-Me        121-122                                                                            70.82                                                                            5.52                                                                             7.08                                    176                                                                              3,4-(CH.sub.2).sub.4                                                                      H           153-155                                                                            69.45                                                                            6.54                                                                             7.31                                    177                                                                              3-CF.sub.3, 4-Cl                                                                          3,4-CHCHCHCH                                                                              160-161                                                                            57.57                                                                            3.79                                                                             5.79                                    178                                                                              3-CF.sub.3, 4-Cl                                                                          4-Cl        167-168                                                                            49.08                                                                            3.07                                                                             5.93                                    276                                                                              3-CF.sub.3, 4-Cl                                                                          H           131-132                                                                            53.20                                                                            3.73                                                                             6.54                                    __________________________________________________________________________

Example 23 1-Benzoyl-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine(Compound 179)

Benzoylchloride (1.41 mL, 12.1 mmol) was added to a solution ofpyridazine (1C) (R₁ =4-Cl: 2.36 g, 12.1 mmol) in toluene. The resultingmixture was heated to reflux for 2 hours, stirred at room temperaturefor 16 hours, dried and concentrated. Column chromatography on silicagel using methylene chloride as an eluent followed by recrystallizationof the desired fractions from ethyl acetate gave the desired compound asa solid: mp 117°-118° C.

Anal. Calc'd for C₁₇ H₁₅ ClN₂ O: C, 68.33; H, 5.07; N, 9.37 Found: C,68.47; H, 4.86 N, 9.42

The following acylated pyridazines listed in Table 6 were preparedessentially by the above procedure, using the appropriate startingmaterials

                                      TABLE 6                                     __________________________________________________________________________     ##STR20##                                                                                                    Analysis                                      Cpd.                                                                             R.sup.1     R.sup.3     mp:(°C.)                                                                    C  H  N                                       __________________________________________________________________________    180                                                                              H           4-Me        89-90                                                                              77.51                                                                            6.48                                                                             9.99                                    181                                                                              4-OMe       4-Me        116-117                                                                            74.09                                                                            6.72                                                                             8.67                                    182                                                                              4-OMe       4-OMe       124-125                                                                            70.33                                                                            6.36                                                                             8.33                                    183                                                                              H           4-OMe       120-121                                                                            73.40                                                                            6.26                                                                             9.46                                    184                                                                              4-OMe       4-Cl        119-120                                                                            65.56                                                                            5.23                                                                             8.49                                    185                                                                              H           3-Cl, 4-Cl  139-140                                                                            60.92                                                                            4.13                                                                             8.41                                    186                                                                              H           3-Cl        88-89                                                                              68.55                                                                            4.90                                                                             9.38                                    187                                                                              H           4-Br        139-140                                                                            59.44                                                                            4.29                                                                             8.11                                    188                                                                              4-OMe       3-Cl        102-103                                                                            65.91                                                                            5.09                                                                             8.58                                    189                                                                              4-OMe       3-Cl, 4-Cl  121-122                                                                            59.52                                                                            4.39                                                                             7.70                                    190                                                                              4-OMe       4-Br        139-140                                                                            57.69                                                                            4.47                                                                             7.44                                    191                                                                              4-Cl        H           117-118                                                                            68.47                                                                            4.86                                                                             9.42                                    192                                                                              4-Cl        4-Me        130-140                                                                            69.31                                                                            5.35                                                                             9.02                                    193                                                                              4-Cl        4-Cl        156-157                                                                            61.44                                                                            4.10                                                                             8.46                                    194                                                                              4-Cl        OMe         140-141                                                                            65.68                                                                            5.14                                                                             8.58                                    195                                                                              4-Cl        4-t-Bu      91-92                                                                              70.98                                                                            6.43                                                                             7.68                                    196                                                                              H           H           110-111                                                                            77.03                                                                            5.99                                                                             10.55                                   197                                                                              H           4-t-Bu      92-93                                                                              78.61                                                                            7.59                                                                             8.68                                    198                                                                              4-Cl        4-Br        168-169                                                                            54.08                                                                            3.66                                                                             7.38                                    199                                                                              4-Cl        3-Cl        118-119                                                                            61.26                                                                            4.12                                                                             8.29                                    200                                                                              4-Cl        3-Cl, 4-Cl  95-96                                                                              55.54                                                                            3.34                                                                             7.44                                    201                                                                              4-OMe       4-t-Bu      123-124                                                                            75.45                                                                            7.33                                                                             7.87                                    202                                                                              4-Cl        4-NO.sub.2  172-174                                                                            59.48                                                                            3.96                                                                             11.95                                   203                                                                              4-F         4-NO.sub.2  179-180                                                                            62.44                                                                            4.29                                                                             12.64                                   204                                                                              4-F         4-Cl        126-127                                                                            64.33                                                                            4.42                                                                             8.83                                    205                                                                              4-F         3-Cl, 4-Cl  112-113                                                                            57.88                                                                            3.45                                                                             7.81                                    206                                                                              4-n-Bu      3-Cl, 4-Cl  144-145                                                                            49.44                                                                            3.05                                                                             6.53                                    207                                                                              4-OMe       4-NO.sub.2  153-154                                                                            63.75                                                                            4.71                                                                             12.36                                   208                                                                              4-OMe       3,4-CHCHCHCH                                                                              133-134                                                                            76.80                                                                            5.63                                                                             8.19                                    __________________________________________________________________________

Example 241-(4-Iodobenzenesulfonyl)-3-(4-dimethylaminophenyl)-1,4,5,6-tetrahydropyridazine(Compound 209)

4-Iodobenzenesulfonyl chloride (0.98 g, 3.25 mmol) was added to asolution of pyridazine (1C) (R₁ =4-N(Me)₂ : 0.67 g, 3.25 mmol) inpyridine. The resulting mixture was stirred at room temperature for 16hours, dried and concentrated. The residue was purified by columnchromatography on silica gel using methylene chloride as an eluent,followed by recrystallization of the desired fractions from ethylacetate to give the desired compound as a solid: mp 203°-205° C.

Anal. Calc'd for C₁₉ H₂₀ IN₃ O: C, 46.06; H, 4.30; N, 8.95 Found: C,46.07; H, 4.18; N, 8.56

The following acylated pyridazines listed in Table 7 were preparedessentially by the above procedure, using the appropriate startingmaterials.

                                      TABLE 7                                     __________________________________________________________________________     ##STR21##                                                                                                    Analysis                                      Cpd.                                                                             R.sup.1     R.sup.3     mp:(°C.)                                                                    C  H  N                                       __________________________________________________________________________    209                                                                              4-NMe.sub.2 4-I         203-205                                                                            46.07                                                                            4.18                                                                             8.56                                    210                                                                              4-NMe.sub.2 4-F         181-182                                                                            59.46                                                                            5.32                                                                             11.25                                   212                                                                              4-NMe.sub.2 4-Cl        172-174                                                                            66.41                                                                            5.72                                                                             12.01                                   213                                                                              4-NMe.sub.2 4-Br        188-200                                                                            50.88                                                                            4.64                                                                             9.56                                    214                                                                              3,4-(CH.sub.2).sub.4                                                                      3-F, 4-F    97-98                                                                              70.91                                                                            5.90                                                                             7.82                                    __________________________________________________________________________

Example 251-(3-Bromo-4-fluorobenzoyl)-3-(3,4-dichlorophenyl)-1,4,5,6-tetrahydropyradazine(Compound 215)

3-Bromo-4-fluorobenzoylchloride (2.0 g, 8.42 mmol) was added to astirred solution of pyridazine (1C) (R₁ =3-Cl, 4-Cl: 1.93 g, 8.42 mmol)in methylene chloride at room temperature under N₂. Triethylamine (2.93mL, 21.1 mmol) was added to the mixture and the progress of the reactionwas monitored by TLC. The resulting mixture was concentratedarylphosphonyl dihalide and purified by column chromatography andrecrystallization to give the title compound as a solid: mp 124°-126° C.

Anal. Calc'd for C₁₇ H₁₂ BrCl₂ FN₂ O₄ S: C, 47.46; H, 2.82; N, 6.51Found: C, 47.64; H, 2.68; N, 6.40

The following acylated pyridazines listed in Table 8 and Table 9 wereprepared essentially by the above procedure, using the appropiratestarting materials.

                                      TABLE 8                                     __________________________________________________________________________     ##STR22##                                                                                               Analysis                                           Cpd.                                                                              R.sup.1                                                                             R.sup.3     mp:(°C.)                                                                    C   H   N                                          __________________________________________________________________________    216 3-Cl, 4-Cl                                                                          3-Cl, 4-Cl  118-119                                                                            51.03                                                                             2.77                                                                              6.84                                       217 3-Cl, 4-Cl                                                                          4-NO.sub.2  181-183                                                                            55.27                                                                             3.22                                                                              11.16                                      218 3-Cl, 4-Cl                                                                          3-CF.sub.3  110-112                                                                            53.78                                                                             3.17                                                                              6.94                                       219 3-Cl, 4-Cl                                                                          3-Cl, 5-Cl  149-151                                                                            50.70                                                                             2.94                                                                              6.77                                       220 3-Cl, 4-Cl                                                                          4-Me        114-115                                                                            62.26                                                                             4.48                                                                              7.75                                       221 3-Cl, 4-Cl                                                                          4-t-Bu      107-109                                                                            64.70                                                                             5.60                                                                              6.98                                       222 3-Cl, 4-Cl                                                                          H           86-87                                                                              61.13                                                                             4.08                                                                              8.28                                       223 3-Cl, 4-Cl                                                                          3-OMe, 4-OMe                                                                              125-127                                                                            58.17                                                                             4.52                                                                              6.88                                       224 4-OMe 3-Cl, 5-Cl  133-134                                                                            59.60                                                                             4.47                                                                              7.68                                       225 3-Cl, 4-Cl                                                                          3,4-CHCHCHCH                                                                              128-130                                                                            65.70                                                                             4.00                                                                              7.18                                       226 3-Cl, 4-Cl                                                                          3-Br, 5-Br  158-169                                                                            41.36                                                                             2.37                                                                              5.70                                       227 H     3-F, 4-F    88-89                                                                              67.92                                                                             4.58                                                                              9.25                                       228 3-Cl, 4-Cl                                                                          3-F, 4-F    134-136                                                                            54.94                                                                             3.07                                                                              7.38                                       229 H     3-Br, 4-F   89-90                                                                              56.77                                                                             3.77                                                                              7.54                                       230 3-Cl, 4-Cl                                                                          3-Br, 4-F   124-126                                                                            47.64                                                                             2.68                                                                              6.40                                       231 4-n-Bu                                                                              3-Cl, 4-Cl  93-94                                                                              64.52                                                                             5.52                                                                              6.89                                       232 H     3-Cl, 5-Cl  101-102                                                                            61.18                                                                             4.13                                                                              8.25                                       __________________________________________________________________________

                  TABLE 9                                                         ______________________________________                                         ##STR23##                                                                                       Analysis                                                   Cpd. R.sup.3  R.sup.5   mp:(°C.)                                                                      C     H     N                                  ______________________________________                                        233  3-Cl, 4-Cl                                                                             5-Me      124-126                                                                              61.91 4.41  7.86                               234  3-Cl, 4-Cl                                                                             5-Me, 5-Me                                                                              108-111                                                                              63.16 4.87  7.53                               235  3-F, 4-F 5-Me       99-100                                                                              68.66 4.87  8.76                               ______________________________________                                    

Example 263-(3,4-Dichlorophenyl)-1-(3,4-difluorothiobenzoyl)-1,4,5,6-tetrahydropyridazine(Compound 236)

Phosphorous pentasulfide (1.20 g, 2.71 mmol) was added to a solution ofpyridazine (3E) (R₁ =3-Cl, 4-Cl; R₃ =3-F, 4-F: 1.0 g, 2.71 mmol) intoluene. The mixture was heated to reflux under N₂ for 2 hours, filteredand concentrated arylphosphonyl dihalide. The resulting residue waspurified by column chromatography on silica gel followed byrecrystallization from ethyl acetate/ether to give the title compound(0.31 g) as a solid: mp 135°-136° C.

Anal. Calc'd for C₁₇ H₁₂ Cl₂ F₂ N₂ S: C, 52.98; H, 3.15; N, 7.27 Found:C, 52.92; H, 2.93; N, 7.02

The following acylated pyridazines listed in Table 10 and Table 11 wereprepared essentially by the above procedure, using the appropriatestarting materials.

                  TABLE 10                                                        ______________________________________                                         ##STR24##                                                                                        Analysis                                                  Cpd. R.sup.1   R.sup.3  mp:(°C.)                                                                       C    H     N                                  ______________________________________                                        237  H         3-Cl, 4-Cl                                                                             151-152 58.32                                                                              3.96  7.96                               238  H         H        95-98   72.76                                                                              5.65  9.91                               239  H         3-F, 4-F 134-136 64.44                                                                              4.52  8.74                               240  H         OMe      112-113 69.64                                                                              5.79  8.87                               241  H         4-Me     156-158 73.15                                                                              6.18  9.15                               242  3-Cl, 4-Cl                                                                              4-NO.sub.2                                                                             189-191 51.72                                                                              3.17  10.40                              243  3-Cl, 4-Cl                                                                              3-Cl, 4-Cl                                                                             132-133 48.83                                                                              2.73  6.57                               244  3-Cl, 4-Cl                                                                              3-Cl, 5-Cl                                                                             134-136 48.92                                                                              2.60  6.42                               245  H         3-Br, 4-F                                                                              142-143 54.46                                                                              3.57  7.05                               246  3-Cl, 4-Cl                                                                              3-Br, 4-F                                                                              135-138 46.04                                                                              2.47  5.93                               247  H         3-Cl, 5-Cl                                                                             132-133 58.42                                                                              3.89  7.73                               ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                         ##STR25##                                                                                        Analysis                                                  Cpd. R.sup.3   R.sup.5   mp:(°C.)                                                                      C    H     N                                  ______________________________________                                        248  3-Cl, 4-Cl                                                                              5-Me      128-129                                                                              59.55                                                                              4.50  7.65                               249  3-Cl, 4-Cl                                                                              5-Me, 5-Me                                                                              142-143                                                                              60.58                                                                              4.67  7.46                               250  3-F, 4-F  5-Me      110-112                                                                              65.33                                                                              4.87  8.47                               ______________________________________                                    

Example 27 Methyl3-(4-butylphenyl)-1,4,5,6-tetrahydropyridazin-1-yl!phenyl phosphonate(Compound 251)

Phenylphosphonic dichloride (0.86 mL, 6.09 mmol) was added dropwise to asolution of pyridazine 1C (R₁ =Bu: 1.31 g, 6.09 mmol) in pyridine at 0°C. The reaction mixture was stirred at 0° C. for 1 h and warmed to roomtemperature. Methanol (3 mL) was added to the resulting mixture and thismixture was stirred at room temperature for 16 h. 2N HCl was added tothe reaction mixture followed by successive washes with methylenechloride. The combined organic extracts were dried (K₂ CO₃),concentrated arylphosphonyl dihalide and purified by columnchromatography on silica gel; followed by recrystallization from ethylacetate/hexane to give the title compound as a solid: (0.25 g): mp74°-76° C.

Anal. Calc'd for C₂₁ H₂₇ N₂ O₂ P: C, 68.08; H, 7.36; N, 7.56 Found: C,67.77; H, 7.20; N, 7.34

The following acylated pyridazines listed in Table 12 were preparedessentially by the above procedure, using the appropriate startingmaterials.

                  TABLE 12                                                        ______________________________________                                         ##STR26##                                                                                        Analysis                                                  Cpd. R.sup.1   R.sup.7   mp:(°C.)                                                                      C    H     N                                  ______________________________________                                        252  H         Me        89-91  64.84                                                                              6.00  8.91                               253  H         Et        88-91  66.07                                                                              6.42  8.69                               254  H         i-Pr      89-92  66.93                                                                              6.74  8.09                               255  3-Cl, 4-Cl                                                                              Et        117-119                                                                              54.46                                                                              4.84  6.97                               256  3-Cl, 4-Cl                                                                              i-Pr      103-104                                                                              55.45                                                                              5.13  6.67                               257  3-Cl, 4-Cl                                                                              cyclopentyl                                                                             115-116                                                                              57.67                                                                              5.42  6.34                               258  4-F       Me        129-131                                                                              61.47                                                                              5.26  8.36                               259  4-F       Et        111-114                                                                              62.51                                                                              5.70  8.39                               260  4-Br      Me        171-172                                                                              51.91                                                                              4.68  6.93                               261  3-CF.sub.3, 4-Cl                                                                        Me        92-93  51.88                                                                              4.18  6.77                               262  3-CF.sub.3, 4-Cl                                                                        Et        89-90  52.92                                                                              4.20  6.35                               263  4-n-Bu    Et        <25    68.50                                                                              7.90  7.14                               264  4-OMe     Me        155-156                                                                              62.85                                                                              6.08  8.05                               ______________________________________                                    

Example 28 6-(4-Amino-3,5-dibromophenyl)-4,5-dihydropyridazin-3-one

(4-Amino-3,5-dibromphenyl)-2,3,4,5-tetrahydropyridazine was prepared asdescribed in Example 2 starting with6-(4-amino-3,5-dibromophenyl)-4,5-dihydropyridazin-3-one and LAH in THFto give a solid which was taken on to the next step without furtherpurification.

The title compound was prepared as described in Example 1 starting withhydrazine and 3-(4-amino-3,5-dibromobenzoyl)propionic acid in ethanol togive a solid: mp 212°-214° C.

Example 29(3-4-Amino-3,5-dibromophenyl)-1-(3,4-dichlorobenzoyl)-1,4,5,6-tetrahydropyridazine(Compound 265)3-(4-Amino-3-bromophenyl)-1-(3,4-dichlorobenzoyl)-1,4,5,6-tetrahydropyridazine(Compound 266)

3,4-dichlorobenzolylchloride (2.74 g, 8.24 mmol) was added to a stirredsolution of pyridazine 1-C (R₁ =3-Cl, 4-Cl: 1.73 g, 8.42 mmol) inmethylene chloride at room temperature under N₂. Triethylamine (3.5 mL)was added to the mixture and the resulting mixture was stirredovernight. 2N HCl was added to the reaction mixture followed bysuccessive washes with methylene chloride. The combined organic extractswere dried (K₂ CO₃), concentrated arylphosphonyl dihalide and passedthrough a column of silica gel using methylene chloride as an eluent.Column fractions containing both Compound 265 and Compound 266 wereconcentrated arylphosphonyl dihalide to give the title compounds as asolids: Compound 265 mp 179°-182° C.

Anal. Calc'd for C₁₇ H₁₃ Br₂ Cl₂ N₃ O: C, 40.34; H, 2.59; N, 8.30 Found:C, 40.30; H, 2.58; N, 7.92

Compound 266 mp 202°-206° C.

Anal. Calc'd for C₁₇ H₁₄ BrCl₂ N₃ O: C, 47.79; H, 3.31; N, 9.83 Found:C, 47.59; H, 3.20; N, 9.41

Example 303-(3,5-Dibromophenyl)-1-(3,4-dichlorobenzoyl)-1,4,5,6-tetrahydropyridazine(Compound 267)

NaNO₂ (0.24 g, 3.43 mmol) was added to a suspension of3-(4-amino-3,5-dibromophenyl)-1-(3,4-dichlorobenzoyl)-1,4,5,6-tetrahydropyridazine(1.0 g, 1.98 mmol, HBr (25%, 3 mL) and water (6 mL)in ethanol (50 mL).The resulting mixture was stirred and heated at a low temperature for1.5 hours. CuBr₂ in HBr (48%, 6 mM) was added to the reaction mixtureand the resulting mixture was stirred for 3 hours at room temperature.Water was added to the reaction and a solid precipitated from thismixture. The solid was purified by column chromatography to give thetitle compound as a white solid: mp 179°-182° C.

Anal. Calc'd for C₁₇ H₁₂ Br₂ Cl₂ N₂ O: C, 41.57; H, 2.47; N, 5.70 Found:C, 41.54; H, 2.39; N, 5.42

Example 313-(3,4-Dichlorophenyl)-1-(2-thienoyl)-1,4,5,6-tetrahydropyridazine(Compound 268)

The title compound was prepared as described in Example 24 starting withpyridazine 1-C (R₁ =3-Cl, 4-Cl: 1.92 g, 8.39 mmol) and 2-thienoylchloride (1.23 g, 8.39 mmol) to give a solid (0.59 g, 21%): mp 116°-118°C.

Anal. Calc'd for C₁₅ H₁₂ Cl₂ N₂ OS: C, 53.09; H, 3.57; N, 8.25 Found: C,53.12; H, 3.38; N, 8.23

Example 323-(3,4-Dichlorophenyl)-1-(2-furoyl)-1,4,5,6-tetrahydropyridazine(Compound 269)

The title compound was prepared as described in Example 24 starting withpyridazine (C) (R₁ =3-Cl, 4-Cl: 1.63 g, 7.1 mmol) and 2-furoylchloride(0.93 g, 7.1 mmol) to give a solid (0.62 g, 27%): mp 97°-98° C.

Anal. Calc'd for C₁₅ H₁₂ Cl₂ N₂ O₂ : C, 55.73; H, 3.75; N, 8.66 Found:C, 55.63; H, 3.79; N, 8.66

Example 334-Bromo-1-(3,4-dichlorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine(Compound 270)

The title compound was prepared as described in Example 22 starting with3-(3,4-difluorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine andbromine to give a solid: mp 168°-169° C.

Anal. Calc'd for C₁₇ H₁₃ BrCl₂ N₂ O: C, 49.55; H, 3.18; N, 6.80 Found:C, 49.34; H, 3.16; N, 6.52

Example 344-Bromo-1-(3-bromo-4-fluorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine(Compound 271)

The title compound was prepared as described in Example 22 starting with1- (3-bromo-4-fluorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine andbromine to give a solid: mp 147°-148° C.

Anal. Calc'd for C₁₇ H₁₃ Br₂ FN₂ O: C, 46.39 H, 2.98; N, 6.37 Found: C,46.07; H, 2.84; N, 6.27

Example 353-(3,4-Dichlorophenyl)-1-(4-pentafluoroethylbenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(Compound 272)

A slurry of3-(3,4-dichlorophenyl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(2.28 g), copper iodide (1.8 g), sodium pentafluoropropionate (1.58 g)and DMF (20 mL) in toluene (20 mL) was distilled at 120° C., until mostof the toluene was removed. The resulting mixture was heated to 155° C.for 2 hours, cooled, poured into water and extracted with methylenechloride. The combined organic extracts were washed with salinesolution, dried with K₂ CO₃ and concentrated arylphosphonyl dihalide.The residue was purified by column chromatography on silica gel usingmethylene chloride/hexane as an eluent to give the title compound as asolid: mp 158°-160° C.

Anal. Calc'd for C₁₈ H₁₃ Cl₂ F₅ N₂ O₄ S: C, 44.36; H, 2.69; N, 5.75Found: C, 44.02; H, 2.68; N, 5.39

Example 363-(3,4-Dichlorophenyl)-1-(4-carbomethoxybenzesulfonyl)-1,4,5,6-tetrahydropyridazine(Compound 273)

A suspension of3-(3,4-dichlorophenyl)-1-(4-carboxybenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(prepared as described in Example 3) and acetyl chloride in methanol washeated to reflux for 6 hours, stirred at room temperature for 72 hours,heated to reflux for another 3 hours and concentrated. The residue waspurified by column chromatography on silica gel using methylene chlorideas an eluent to give the title compound as a solid: mp 146°-152° C.

Anal. Calc'd for C₁₈ H₁₆ Cl₂ N₂ O₄ S: C, 50.58; H, 3.78; N, 6.55 Found:C, 50.58; H, 3.77; N, 6.42

Example 371-(4-Aminobenzenesulfonyl)-3-(3,4-dichlorophenyl)-1,4,5,6-tetrahydropyridazine(Compound 274)

(3,4-Dichlorophenyl)-1-(4-nitrobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(4.7 g, 11.3 mmol) was suspended in acetic acid at 80° C. Iron filings(3.17 g) were added to this suspension and the resulting reactionmixture was heated at 60°-80° C. until the TLC did not show any startingnitro compound. The mixture was filtered concentrated and purified bycolumn chromatography and recrystallization to give the title compoundas a solid: mp 232°-234° C.

Anal. Calc'd for C₁₆ H₁₆ Cl₂ N₃ O₂ S: C, 50.00; H, 3.94; N, 10.93 Found:C, 49.81; H, 3.61; N, 10.59

Example 383-(3,4-Dichlorophenyl)-1-(4-methylsulfonylbenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(Compound 2751)

The title compound was prepared as described in Example 6 starting with3-(3,4-dichlorophenyl)-1-(4-thiomethylbenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(0.29 g, 0.70 mmol) and MCPBA (0.36 g, 0.83 mmol) to give a solid: mp181°-183° C.

Anal. Calc'd for C₁₇ H₁₆ Cl₂ N₂ O₄ S₂ : C, 45.64; H, 3.61; N, 6.26Found: C, 45.58; H, 3.50; N, 6.17

Example 39

A solution of bromine (8.75 mL) in acetic acid (25 mL) was addeddropwise to a mixture of ethyl 4-oxo-4-(4-aminophenyl)butyrate which isprepared as disclosed by M. Thyes et al., J. Med Chem, 26, 800 (1983),(30 g 135.7 mmol) and potassium thiocyanide (30.6 g) at room temperatureunder nitrogen. The resulting exothermic reaction was allowed to subsideand the mixture was stirred for 15 minutes. The reaction was quenchedwith cold water and the resulting precipitate was filtered, washed withwater and dried to give the intermediate thiocyanate as a solid (mp 140°C.). This solid was added to solution of sodium sulfate nonahydrate (70g) in water (200 mL) and heated to reflux for 1 hour under nitrogen. Theresulting mixture was cooled to -10° C. and acidified to pH 5 withacetic acid. Ethyl-4-oxo-4-(4-amino-3-mercaptophenyl)butyrateprecipitated out of this mixture as a solid in 93% yield.

Ethyl-4-oxo-4-(4-amino-3-mercaptophenyl)butyrate (22.5 g) was added to a0.13M sodium bicarbonate solution (300 mL). The mixture was cooled to 5°C. and chloroacetyl chloride (9 mL) was added dropwise. The resultingmixture was stirred at 5° C. for 15 minutes, heated to reflux for 30min, cooled with ice-water and acidified to a pH of 2 with 6N HCl.Ethyl-4-oxo-1,4(2H)-benzothiazin-7-yl)butyrate precipitated out of thissolution as a solid.

Sodium hydride (60 % in oil: 2.15 g) was added at room temperature undernitrogen to a stirred solution ofethyl-4-oxo-1,4(2H)-benzothiazin-7-yl)butyrate (10 g) in DMF (100 mL).After 20 minutes, methyl iodide (3.34 mL) was added and the reactionmixture was stirred for 2 hours at room temperature and cooled to 0° C.Ethyl-4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzothiazin-7-yl)butyrateprecipitated out of this solution as a solid (in 76% yield ) (mp72°-73.5° C.). Anhydrous hydrazine (0.5 mL) was added to a suspension ofethyl-4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzothiazin-7-yl)butyrate (1.0g). The mixture was heated to reflux for 72 hours and cooled to yieldethyl-4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzothiazin-7-yl)-2,3,4,5-tetrahydropyridazin-3-oneas a solid (0.16 g) (mp 235°-237° C.).

MCPBA (6.47 g) was added to a solution ofethyl-4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzothiazin-7-yl)butyrate(6.47 g) in 8methylene chloride at room temperature under nitrogen. Thereaction mixture was stirred for 2 hours, concentrated andrecrystallized from ether/ethyl acetate to giveethyl-4-oxo-4-(3,4-dihydro-4-methyl-1,1,3-trioxo-1,4(2H)-benzothiazin-7-yl)butyrate(4.79 g).

A solution ofethyl-4-oxo-4-(3,4-dihydro-4-methyl-1,1,3-trioxo-1,4(2H)-benzothiazin-7-yl)butyrate(4.79 g) and hydrazine (1 mL) was heated to reflux for 1 h undernitrogen. The reaction mixture was stirred overnight at room temperatureto giveethyl-4-oxo-4-(3,4-dihydro-4-methyl-1,1,3-trioxo-1,4(2H)-benzothiazin-7-yl)-2,3,4,5-tetrahydropyridazin-3-one(2.95 g) as a solid.

Example 401-(4-Aminobenzenesulfonyl)-3-(3-trifluoromethyl-4-Chlorophenyl)-1,4,5,6-tetrahydropyridazine(Compound 277)

(4-chlorophenyl)-1-(4-nitrobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(2.12 g, 5.0 mmol) was suspended in acetic acid at 80° C. Iron filings(3.0 g) were added to this suspension and the resulting reaction mixturewas heated at 80° C. for 30 minutes and filtered. The solvent wasremoved at reduced pressure and the residue taken up in methylenechloride and filtered through silica gel. The eluent was evaporated andthe residue recrystallized from ether to give (0.9 g) the titlecompound: mp 205°-206° C.

Anal. Calc'd for C₁₆ H₁₆ ClN₃ O₂ S: C, 54.92; H, 4.61; N, 12.01 Found:C, 54.92; H, 4.64; N, 12.17

Example 413-(4,5-Dibromo-2-thienyl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine(Compound 278)

2,3-Dibromothiophene (15.3 g, 63 mM) and succinic anhydride (63 g, 63mM) were dissolved in nitrobenzene (250 mL) and the mixture cooled to 0°C. Aluminum chloride (18.4 g) was added to this mixture. The red mixturewas kept below 10° C. for three hours. Water (38 mL) and HCl (9 mL) wereadded. The solution was extracted with 1M sodium hydroxide and the basicextracts were combined and washed with dichloromethane. The aqueoussolution was then acidified with diluted HCl solution and extracted withdichloromethane. The organic solution was dried over magnesium sulfate,evaporated and the residue 4-(4,5-dibromo-2-thienyl)-4-oxobutyric acid(14.8 g) was dissolved in ethanol. Hydrazine (3.63 g) was added and themixture was heated at reflux for 2 h. The mixture was cooled and theproduct collected by filtration and dried to give 11.3 g of3-(4,5-dibromo-2-thienyl)-1,4,5,6-tetrahydropyridazin-6-one.

(4,5-Dibromo-2-thienyl)-1,4,5,6-tetrahydropyridazin-6-one (2.75 g, 8.14mM) was dissolved in THF (80 mL) and diborane (1M in THF solution) (16.3mL, 16.3 mM) added. After stirring the solution for 0.5 h the excessreagent was quenched with 20% sodium hydroxide solution and the mixturewas filtered The filtrate was evaporated to give the pyridazine compoundas a yellow oil (2.78 g) which was used in the next step withoutpurification.

(4,5-Dibromo-2-thienyl)-1,4,5,6-tetrahydropyridazine (0.92 g, 2.83 mM)was dissolved in pyridine and pipsyl chloride (0.8 g, 2.83 nM) added tothe solution. The mixture was stirred at room temperature for 3 hoursthen poured into 3N HCl and extracted with dichloromethane. The organicfraction was dried over magnesium sulfate and evaporated. The residuewas chromatographed on silica gel and the fractions containing productwere combined, evaporated to dryness, and recrystallized frommethanol/chloroform giving 0.9 g of3-(4,5-dibromo-2-thienyl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyridazinewith mp 155°-156° C.

Anal. Calc'd for C₁₄ H₁₁ Br₂ IN₂ O₂ S₂ : C, 28.50; H, 1.88; N, 4.75Found: C, 28.53; H, 1.90; N, 4.68.

Example 423-(5-Bromo-2-thienyl)-1-(3,4-dichlorobenzoyl)-1,4,5,6-tetrahydropyridazine(Compound 279)

(5-Bromo-2-thienyl)-1,4,5,6-tetrahydropyridazin-6-one was prepared as inExample 41 condensing 2-bromothiophene and succinic anhydride withaluminum chloride followed by reaction with hydrazine in ethanol.

(5-Bromo-2-thienyl)-1,4,5,6-tetrahydropyridazin-6-one (4.0 g, 15 mM) wasdissolved in THF (80 mL) and diborane (1M in THF solution) (32 mL, 32mM) was added. After stirring for 0.5 h the excess reagent was quenchedwith 20% sodium hydroxide solution and the mixture was filtered. Thefiltrate was evaporated to give the pyridazine as a yellow oil (3.92 g)which was used in the next step without purification.

(5-Bromo-2-thienyl)-1,4,5,6-tetrahydropyridazine (1.0 g, 4.1 mM) wasdissolved in CH₂ Cl₂ (40 mL) and 3,4-dichlorobenzoyl chloride (0.85 g,4.1 mM) and trimethylamine (40 mL) were added to the solution. Themixture was stirred at 22° C. for 3 h then poured into 1N HCl. Theorganic layer was dried over MgSO₄ and evaporated. The residue wasrecrystallized from methanol/IPA to give 0.9 g of product with mp138°-140° C.

Anal. Calc'd for C₁₅ H₁₁ BrCl₂ N₂ OS: C, 43.09; H, 2.65; N, 6.70 Found:C, 43.30; H, 2.73; N, 6.60

Example 433-(2-Thienyl)-1-(3,4-dichlorobenzoyl)-1,4,5,6-tetrahydropyridazine(Compound 280)

(2-Thienyl)-1,4,5,6-tetrahydropyridazin-6-one (4.0 g, 22 mM) wasdissolved in THF and lithium aluminum hydride (40 mL, 1N solution inTHF) was added at 15° C. The mixture was allowed to warm to roomtemperature and stir for 1 h. Excess reagent was destroyed with 15%sodium hydroxide and the mixture was filtered and evaporated to drynessto give 3.0 g of a light yellow oil which crystallized upon standing inair.

(2-Thienyl)-1,4,5,6-tetrahydropyridazine (1.0 g, 5.56 mM) was dissolvedin dichloromethane (150 mL) and triethylamine (100 mL) was addedfollowed by 3,4-dichlorobenzoyl chloride (1.17 g, 5.56 mM). The mixturewas stirred at room temperature for 18 h and evaporated to dryness. Theresidue was chromatographed on silica gel and eluted with CH₂ Cl₂ togive 1.1 g of white solid with mp 124°-125° C.

Anal. Calc'd for C₁₅ H₁₂ Cl₂ N₂ OS: C, 53.11; H, 3.56; N, 8.26 Found: C,52.75; H, 3.54; N, 7.91.

Example 441-(4-Iodobenzenesulfonyl)-3-(3-trifluoromethyl-4-chlorophenyl)-6-methyl-1,4,5,6-tetrahydropyridazine(Compound 281)

4-Phenylurazole (4.74 g, 0.027 mmol) was dissolved in dry DMSO andcooled to 10° C. under nitrogen. Tosylisocyanate (5.39 g, 0.027 mmol)was added and the mixture allowed to come to room temperature.4-Chloro-3-trifluoromethylphenyl-1,3-pentadiene was added slowly whilethe solution was cooled to 15° C. After 30 min the reaction was dilutedwith chloroform (500 mL) and washed with 5% NaOH solution. The organiclayer was dried over magnesium sulfate and filtered. The solvent wasremoved at reduced pressure and the residue used in the next step.

The above residue (3.0 g) was dissolved in THF and one equivalent ofdiborane added slowly at 0° C. When addition was complete the mixturewas heated to 45° C. for 2 h. Propionic acid was added and thetemperature raised to 80° C. for 1.5 h. Water and saturated NaHCO₃solution was added and the mixture extracted with ether anddichloromethane. The combined organic layers were dried over Na₂ SO₄,filtered and evaporated to dryness.

The above residue (1 g) was dissolved in ethylene glycol and fiveequivalent of potassium hydroxide and heated to 110° C. for 3 h. Water(400 mL) was added and the mixture extracted with ether anddichloromethane. After drying (Na₂ SO₄) and filtration, the solvent wasremoved at reduced pressure to give 700 mg of product.

3-(3-trifluoromethyl-4-chlorophenyl)-6-methyl-1,4,5,6-tetrahydropyridazine(700 mg) was combined with 4-iodobenzenesulfonyl chloride (558 mg) andheated to 105° C. for 3 h. Dichloromethane was added and the solutionwashed with water, 10% HCl, sat'd NaHCO₃ and brine. The organic layerwas dried (Na₂ SO₄), filtered and solvent removed at reduced pressure togive a residue which was recrystallized from acetone/hexane to give 148mg of the title compound with mp 157°-158° C.

Anal. Calc'd for C₁₈ H₁₅ ClF3IN₂ O₂ S: C, 39.83; H, 2.79; N, 5.16

C, 39.56; H, 2.65; N, 5.19

Example 45 1-(4Iodobenzenesulfonyl)-3-(3,4-dichlorophenyl)-6-methyl1,4,5,6-tetrahydropyridazine (Compound 282)

The method of example 44 was employed using3,4-dichlorophenyl-1,3-pentadiene to give the desired product with mp194°-196° C.

Anal. Calc'd for C₁₇ H₁₅ Cl2IN₂ O₂ S: C, 40.10; H, 2.97; N, 5.50 C,39.97; H, 2.80; N, 5.46

Methods for the Determination of Progestational or AntiprogestationalActivity Progestin Receptor Binding

A progestin initiates a biological response by first binding to aprogestin receptor. Affinity for progestin receptors was determined bymeasuring the ability of compounds to displace a progestin radioligandfrom those receptors in vitro. Cytosolic progestin receptor wereobtained by mixing rabbit uterine tissue with a Tris buffer 0.1MTris-Hcl, 1 mM Na₂ EDTA, 1 mM dithiothreotol, 1 mM sodium molybdate, 1%glycerol, pH 7.4!. The tissue/buffer mixture was homogenized underice-cold conditions. The homogenate was then centrifuged and thesupernatant (cytosol preparation) was decanted and stored at -70° C. andthawed prior to use. The competitive binding assay was performed bymixing ³ H-R5020, a progestin radioligand, with cytosol preparation andvarious concentrations of test compounds (prepared in DMSO with a final5% DMSO concentration). This mixture was then incubated at 4° C. forabout 18 hours. Non-specific binding was determined using an unlabelledligand in excess. After the incubation period, the radioligand bound toreceptor was separated from free radioligand using dextran-coatedcharcoal. The amount of bound radioligand was then determined by liquidscintillation counting. The data were expressed as the concentration oftest compound that displaced 50% of the radioligand from the receptor(IC₅₀)

Aspects of the application used in this procedure are described in thefollowing: J. L. McGuire et al., Biochemistry 13, 319, 1974.

Ex Vivo Progestational Test

The progestational activity of the compounds was accessed by theirability to stimulate proliferation of human breast carcinoma cells.Proliferation was measured as the ability to stimulate ³ H-thymidineincorporation into these cells in vitro. Human T47D breast carcinomacells (American Type Tissue Collection #133-HTB) were maintained inmedia consisting or RPMI 1640 supplemented with 10% fetal bovine serum,10 ug/ml insulin, 10 U/ml pennicillin, 100 ug/ml streptomycin, and 2 mML-glutamine. Monolayer cell cultures were trypsinized and washed inassay media consisting of phenol red-free RPMI 1640 supplemented with 5%charcoal-stripped, fetal bovine serum, and the other ingredients listedabove. Cells were then plated in a 96-well plate. After a 48-hourincubation period at 37° C., the conditioned media was removed andreplaced with fresh media containing test compounds in DMSO (0.1% DMSOfinal concentration). The cell cultures were incubated for 18 to 20hours at 37° C. ³ H-thymidine was then added to each well and the cellcultures were incubated at 37° C. for an additional 4 hours. Labellingwas stopped by addition of un labelled thymidine. The cultures werewashed twice, trypsinized and then harvested onto a filter mat.Incorporated ³ -H-thymidine was measured by liquid scintillationcounting. Data was expressed as a percent stimulation above controllevel which was set at 100%. An SC₂₀₀ value was calculated as theconcentration of test material needed to stimulate ³ H-thymidineincorporation 200% of control.

Aspects of the application of the procedure used are described in thefollowing: C. Christensen, D. Gunter, D. Saunders and V. Malviya,Gynecol. Oncol., 28, 25 (1987); J. Puzas, R. Drivdahl, G. Howard and D.Baylink, Proc. Soc. Exp. Biol. Med., 166, 113 (1981); and I. Keydar, L.Chen, S. Karby, F. Weiss, J. Delarea, M. Raduy, S. Chaitcik and H.Brenner, Eur. J. Cancer, 15, 659 (1979)

Ex Vivo Antiprogestational Test

The same test system as above may be used to determineantiprogestational activity by inducing a positive response with anappropriate amount of a standard progestin such as R5020 and diminishingthat response with increasing concentrations of an antiprogestin. Theconcentration of antiprogestin needed to reduce the progestationalactivity by 50% is designated as the ED₅₀ concentration.

In Vivo Progestational Test (McGinty Test)

Progestational activity was measured in vivo by the ability to stimulatethe rabbit endometrium after injection into the uterine horn.

Immature New Zealand White female rabbits were injected subcutaneouslyfor 6 days with 5.0 μg of 17β-estradiol per day. On the 7th day therabbits were anesthetized, the abdomen opened and a uterine hornexposed. Two ligatures were placed around a segment of the uterus 3-4 cmlong, leaving the major blood vessels outside the ties.

The upper ligature was tied tightly, and the lower one was left loose. Aneedle attached to a syringe was injected in the uterus below the secondligature and up into the area between the two ligatures. As the testmaterial was injected, the ligature was tightened and held tight so thatthe needle was withdrawn without the loss of fluid. The second ligaturewas secured and the abdomen closed.

The rabbits were sacrificed approximately 72 hours after the injection.The uteri were removed, fixed in 10% buffered formalin, sectioned at 6μ,and stained with hematoxylin and eosin. The evaluation for endometrialproliferation was made according to a McPhail Index. Each slide wasgraded for each rabbit on a 0 (no response)-4 (maximum response) scale.The compounds active in this assay are tabulated in Table 13.

Aspects of the application of the procedure used are described in thefollowing: D. McGinty, C. Anderson, and N. McCullough, Endocrinology,24, 829 (1939); M. McPhail, J. Physiol., 82, 145 (1934); and G. Pincus,and N. Werthessen, Am. J. Physiol., 120, 100 (1937).

In Vivo Progestational Test (Clauberg Test)

Progestational activity was also measured in vivo by the abiity tostimulate the rabbit endometrium after either oral or parenteraladministration.

Immature New Zealand female White rabbits were primed with a dailysubcutaneous injection, for 6 days, with 5 micrograms of 17β-estradiolin sesame oil. Starting on the 7th day, the rabbits were given the testmaterial daily for five days. The rabbits were sacrificed approximately24 hours after the last administration, and the uteri were excised,trimmed and weighed. Portions of both uterine horns were fixed in 10%neutral formalin, sectioned at 6μ and stained with hematoxylin andeosin. Progestational activity was assessed as described above for theMcGinty Test. The compounds active in this assay are tabulated in Table13

Aspects of the application used in this procedure are described in thefollowing: M. K. McPhail, J. Physiology 83:145, (1934).

Method for the Determination of Bone Growth Activity Osteoblast CellProliferation

Compounds of the present invention have utility to treat osteoporosisthrough enhancement of bone calcification rather than traditionalapproaches which generally involve inhibition of bone degeneration orresorption. The compounds of the present invention have been evaluatedas stimulators of proliferation of osteoblast cell and chick calivariabone organ culture which is predictive of enhancement of bone mass andbone formation in vivo.

The action of select compounds to stimulate osteoblast growth wasmeasured in culture by estimating the rate of DNA synthesis by the rateof ³ H-thymidine incorporation into DNA. Only cells undergoing mitosissynthesized new DNA and thus only these cells incorporated theradiolabelled DNA-specific thymidine. The stimulation of theproliferation and differentiation of bone-forming cells, osteoblasts,was a prerequisite for an increase in bone formation and bone mass. Theability of agents to increase osteoblast proliferation anddifferentiation can be predicted by their action on culturedosteoblast-line cells in vitro. In this test, mouse (MC3T3-E1) and human(TE-85) osteoblast-line cells (American Type Tissue Culture Collection,#CRL 1543, Rockville, Md. cloned by Sudo et al., Koriyama, Japan) werecultured in vitro and the effect of various agents were tested onosteoblast cell proliferation. Cells were harvested from large cultureflasks where they were allowed to grow to near confluency using trypsin.The cells were plated into 96 well culture plates, 1600 cells in 100 μLper well in Dulbencos Modified Eagle's Medium (DMEM) with 25 mM HEPESbuffer, L-glutamine (584 mg/L); D-glucose (4.5 g/L) supplemented withfetal bovine sera (10%); penicillin (100 units/mL) and streptomycin (100mcg/mL); sodium pyruvate (10 μM final concentration). The cells wereallowed to plate overnight in DMEM containing 10% fetal bovine sera at37° C. in an atmosphere of 5% CO2/95% air. Following their placementinto 96 well culture plates all the osteoblast-line cells, either theMC3T3-E1 or the TE-85 cell lines, were allowed an additional 24 hourspreincubation period in media containing only 0.1% fetal bovine sera.

The next day the test compounds were added and screened atconcentrations ranging from 10⁻¹⁴ to 10⁻¹⁶ M depending on the study.Twenty hours later, a 20 μL aliquot of media containing 0.4 μCi of ³H-thymidine was added to each culture well. The cells were thenincubated an additional 4 hours. The incubation was terminated byaspirating the media and washing with HBSS (Hank's Balanced SaltSolution). The cells were then treated with 100 μL of 0.5% trypsin and5.3 mM EDTA for 30 minutes at room temperature. The cells were thenaspirated onto glass fiber filter and washed with water. Theradioactivity on the filters was quantified by liquid scintillationspectroscopy. The rate of ³ H-thymidine incorporation into DNA was thenutilized as an index of cell proliferation. The results are shown inTable 13 expressed as % times control where the control is 100%. A valuegreater than 110 was considered statistically significant, and (providemore preferred values).

Aspects of the application of the procedure used are described in thefollowing: J. E. Puzas, R. H. Drivdahl, A. G. Howard, and D. J. Baylink,Proc. Soc. Exper. Biol. Meal., 166, 113 (1981); and (provide otherreferences).

Central Nervous System Receptor (³⁵ S-TBPS(t-Butylphosphothionate))Binding

The biological test used to generate the data involves the binding of aligand to a site on the GABA_(A) receptor. The ligand is ³H-TBPS(tertbutylphosphothionate), which binds to a site within the Cl⁻channel domain of the receptor. Steroids affect the binding of ³ H-TBPSto this site by inducing a conformational change in the receptor at asite allosteric to the TBPS binding site. This conformational change caneither increase or decrease the binding of TBPS. GABA itself is known tohave similar effects on TBPS binding. The effect of a particular steroidon TBPS binding to Central Nervous System (CNS) membrane preparationsdepends on what region of the CNS the membranes (receptors) are derivedfrom. Further GABA can markedly affect the activity of asteroid. If GABAincreases the potency (affinity) of asteroid, this is interpreted as anindication that the steroid has a positive modulatory effect on theactivity of GABA. Such a compound is expected to be usefultherapeutically for treating anxiety or epilepsy.

The procedure used to test the compounds of the present invention isessentially that of R. P. Shank and W. J. Baldy, J. Neurochem., 55, 541(1990).

Procedure

Charles River, male Wistar rats (virus-free) (160-280 g) were used. Therats were group housed for approximately one week and given food andwater ad libitum. Animals had equal hours of dark and light (12--12).

Test compounds (approximately 1 mg) were dissolved in the appropriatevolume of distilled water to yield a 0.2 mM stock solution. Compoundsthat were not water soluble were dissolved in DMF (and/or NaOH or HCl)to a concentration of 20 mM, and then diluted to the stock concentrationof 0.2 mM in distilled water. The stock solutions were then diluted indistilled water to the working concentrations used in the experiment.

Rats were sacrificed by cervical dislocation, and the brains wererapidly excised on an ice-cold parafilm-covered petri dish. Tissue fromthree areas of the brain was typically used: cerebral cortex,cerebellum, and brain stem (mesencephalon, medulla, and pons). Thetissue from each area was homogenized in 20-40 volumes of NaHEPES (10mM) buffered sucrose (0,3M) solution (made fresh weekly) with six fullstrokes on a motor-driven Teflon pestle/glass homogenizer. Thehomogenate was then centrifuged at 1000×g for 10 minutes and theresulting supernatant was recentrifuged at 42,000×g for 10 minutes. Thesupernatant from this spin was discarried. The resulting pellet wasresuspended in 20-40 volumes of phosphate buffer and preincubated for 1hour at 23° C. Following the incubation, the homogenate was centrifugedat 48,000×g for 10 minutes. The resulting pellet was resuspended in25-30 volumes of 3 mM phosphate buffer (made fresh weekly by mixing 1MK₂ HPO₄ (6 mL) into 1.5 L of distilled water, adjusting to a pH 7.4 with1M KH₂ PO₄, and extending to 2 L) and kept on ice.

Incubation Procedure

Each 13×100 mm glass tube received 1.25 mL phosphate buffer, 0.2 mLNaCl, 0.1 mL distilled water, 0.1 mL ³⁵ S-TBPS (working concentration ofapproximately 3 nM (4.5-5.0×10⁴ DPM/0.1 mL)), 0.1 mL of the testcompound and 0.25 mL of membrane suspension for a total volume of 2 mL.Samples tested in the presence of GABA received 0.1 mL of 0.02 mM GABA(made fresh) and no water. Typically, half of the samples received GABA.Control samples received an additional 0.1 mL of water in place of thetest compound, and the blanks received 0.1 mL of the 2 mM GABA solution(made fresh). The reaction was stated by the addition of the membranematerial. The samples, in groups of 12, are then immediately vortexedand incubated at 25° C. for 10 minutes. The reaction was terminated byrapid vacuum filtration through pre-wet LKB FG/B Filtermats mounted on aSkatron Cell Harvester designed to operate with the LKB Betaplatesystem. The samples were rinsed twice with approximately 2 mL ofice-cold 10 mM NaHEPES wash buffer (made fresh weekly). Following thefiltration, the Filtermats were dried in a microwave oven (3 minuteseach side). LKB Betaplate scintillation fluid (0.1 mL) was added to eachof the 96 sample "spots" on the Filtermat which was then placed in asolvent-resistant plastic bag, heat sealed, and counted in an LKBBetaplate scintillation counter.

Data Analysis

The specific binding varies with the area of the brain, and typicallyrepresents approximately 78% of the total binding in the cortex, 64% inthe cerebellum without GABA present, 55% in the cerebellum with GABA,and 52% in the brain stem. The nonspecific binding was determined using10 μM GABA. The counts per minute (CPM's) for the blank are averaged andsubtracted from the samples and controls. The CPM's for the samples andcontrols are then averaged.

Calculation of Percent Inhibition

Percent inhibition is calculated according to the equation: ##EQU1##

                                      TABLE 13                                    __________________________________________________________________________    Osteoblast Cell Proliferation.sup.1                                                                 Progestational Effect                                   Cpd                                                                              10.sup.-6                                                                        10.sup.-7                                                                        10.sup.-8                                                                        10.sup.-9                                                                        10.sup.-10                                                                       GABA.sup.2                                                                        IC50.sup.3                                                                         T47D.sup.4                                                                        ED50.sup.5                                                                        In-vivo.sup.6                              __________________________________________________________________________    1                 8.7 1.33 46      C,M                                        2  105                                                                              119                                                                              99 91 77 >11 3000                                                    3  92 110                                                                              115                                                                              138                                                                              118    10000                                                   4  108                                                                              111                                                                              155                                                                              153                                                                              158    201                                                     5  89 106                                                                              124                                                                              108                                                                              114    5.3      81                                             6  81 97 106                                                                              114                                                                              121    15                                                      9  65 94 128                                                                              102                                                                              119    362                                                     10 91 90 123                                                                              115                                                                              139    1050                                                    11 106                                                                              135                                                                              156                                                                              131                                                                              154    20                                                      12 118                                                                              115                                                                              114                                                                              131                                                                              135                                                                              0.7 1    153     C,M                                        13 88 109                                                                              114                                                                              109                                                                              152    9                                                       14 96 109                                                                              118                                                                              136                                                                              139    7                                                       15 94 108                                                                              114                                                                              123                                                                              123    6.2  10000                                              16                    4.2                                                     17                    48                                                      18                    204                                                     19                    61                                                      20                    56                                                      21                    42   10000                                              22 86 78 66 59 40     0.54 10000                                                                             154                                            23                    3000                                                    24                    308                                                     25 87 106                                                                              101                                                                              99 90     49                                                      26                    451                                                     27                    65                                                      28                    3140                                                    29                    244                                                     30                    22                                                      31                    4                                                       32 89 103                                                                              105                                                                              111                                                                              118    45                                                      33 96 107                                                                              117                                                                              127                                                                              152    9                                                       34 87 102                                                                              105                                                                              114                                                                              114    3            M                                          35 82 101                                                                              123                                                                              150                                                                              154    3.01         M                                          36                    11.5                                                    37                    12.9                                                    38 76 73 54 49 37     5.29     545                                            39 92 94 84 115                                                                              99 3.2 0.7  100     C,M                                        40 78 90 71 58 53     1.18 26      C,M                                        41 138                                                                              158                                                                              166                                                                              144                                                                              116    1.96 4000    M                                          42 135                                                                              144                                                                              155                                                                              146                                                                              166    0.97 321     M                                          43 93 92 99 98 85     3.3                                                     44 86 107                                                                              105                                                                              95 87     30.8                                                    45 108                                                                              97 123                                                                              135                                                                              95     14.2                                                    46                    15.0                                                    47 109                                                                              112                                                                              113                                                                              115                                                                              123    20.1                                                    48                    266                                                     49                    127                                                     50                    316                                                     51 119                                                                              120                                                                              144                                                                              126                                                                              158    203                                                     52                    42                                                      53                    2198                                                    54                    780                                                     55                    21.9                                                    56                    85.2                                                    57                    189                                                     58                    444                                                     59                    455                                                     60                    191                                                     61                    435                                                     62                    157                                                     63 101                                                                              103                                                                              99 77 97     118                                                     64 116                                                                              115                                                                              121                                                                              128                                                                              137                                                                              >11 550                                                     65 90 98 94 88 80     57                                                      66                    375                                                     67                    126                                                     68                    13.4                                                    69                >11 10000                                                                              10000                                              70                >11 10000                                                   71 110                                                                              114                                                                              99 103                                                                              98 0.77                                                                              10000                                                   72 113                                                                              119                                                                              129                                                                              120                                                                              123                                                                              >11 10000                                                   73                3.4 10000                                                                              10000                                              74                2.2 10000                                                                              10000                                              75                0.21                                                                              10000                                                   76                1.1 10000                                                   77                    1.47 286     C,M                                        78                    2.44 10000   C,M                                        79                    0.9  10000                                                                             406                                            80                    0.79 85      M                                          81    110                                                                              119                                                                              119                                                                              128    16.5                                                    82                    2.95 608     M                                          83                    4.83                                                    84 108                                                                              119                                                                              130                                                                              127                                                                              122                                                                              >11 1000                                                    85 99 80 76 54 48     1000                                                    86 100                                                                              114                                                                              94 103                                                                              101                                                                              >11 228                                                     87 120                                                                              115                                                                              125                                                                              117                                                                              127    82.2                                                    88 97 109                                                                              89 74 62 1.08                                                                              10.2                                                    89 115                                                                              97 113                                                                              106                                                                              98     21.6                                                    90 90 95 68 68 42 >11 71.7                                                    91                    2.39     115                                            92                    23.9                                                    93                    11.1                                                    94 110                                                                              85 90 110                                                                              130    14.6                                                    95                    10.2 10000                                              96                    12.1                                                    97                    0.99 92      C                                          98                    2.5                                                     99                    21                                                      100                   23                                                      101                   195                                                     102                   9                                                       103                   149                                                     104                   0.85 76                                                 105                   1.87 1070                                                                              125                                            106                   7.11                                                    107                   7.45                                                    108                   3.35                                                    109                   1.09 1620                                                                              10000                                          111                   16   10000                                              112                                                                              109                                                                              91 134                                                                              1169                                                                             119    371                                                     113                                                                              66 94 102                                                                              102                                                                              90     27.6                                                    114                   6.5                                                     115                   2.09 72      C                                          116                   8.77                                                    117                   4.97                                                    118                   5.56                                                    119                   2.53 868                                                120                   13.3 831                                                121                                                                              120                                                                              123                                                                              122                                                                              120                                                                              181                                                            122                   47                                                      123                   557                                                     125               10  6.66 166     C                                          126                   7.14                                                    127                   4.04                                                    128                   14.2                                                    129                   4.94                                                    130                   2.31                                                    131               >11 17.4                                                    132               >11 7.5      779                                            136                   70       75                                             138                   341                                                     141                   396                                                     142                   1620                                                    143                   1380                                                    144   112                                                                              122                                                                              117                                                                              108    71.7                                                    145                   100                                                     146                   1000                                                    152                                                                              87 123                                                                              124                                                                              149                                                                              161    175                                                     153                                                                              85 115                                                                              83 99 103    636                                                     154                                                                              97 111                                                                              107                                                                              124                                                                              115    819                                                     156                                                                              127                                                                              124                                                                              126                                                                              136                                                                              183    1000                                                    157                                                                              107                                                                              108                                                                              113                                                                              111                                                                              128    750                                                     158                                                                              105                                                                              102                                                                              122                                                                              114                                                                              119    3000                                                    159                                                                              97 100                                                                              91 97 105    1383                                                    160                   32                                                      161                                                                              76 95 113                                                                              122                                                                              112    3000                                                    162                   3                                                       167                                                                              126                                                                              109                                                                              136                                                                              144                                                                              165    5.93                                                    168                                                                              67 82 82 76 109                                                            169                                                                              128                                                                              131                                                                              133                                                                              134                                                                              195                                                            170                                                                              68 98 108                                                                              108                                                                              108                                                                              >11 2.15 4000                                               171                                                                              72 110                                                                              121                                                                              118                                                                              129                                                            172                                                                              134                                                                              108                                                                              103                                                                              106                                                                              113    32                                                      174                   22.8 10000                                              175                   6.2                                                     176                                                                              59 94 109                                                                              113                                                                              109                                                                              >11                                                         177                   528                                                     178                   5.18 164                                                182                                                                              95 108                                                                              118                                                                              139                                                                              115                                                                              >11 100000                                                  183                                                                              88 133                                                                              131                                                                              136                                                                              135    100000                                                  184                                                                              84 102                                                                              113                                                                              146                                                                              131                                                                              >11 100000                                                  185                                                                              98 136                                                                              147                                                                              131                                                                              128    3560 10000                                              188                                                                              105                                                                              129                                                                              130                                                                              135                                                                              137    100000                                                  189                                                                              89 112                                                                              98 122                                                                              128    100000                                                  190                                                                              121                                                                              135                                                                              130                                                                              139                                                                              158    100000                                                  191                                                                              86 133                                                                              126                                                                              133                                                                              123    100000                                                  192                                                                              115                                                                              131                                                                              128                                                                              132                                                                              148    100000                                                  193                                                                              107                                                                              161                                                                              162                                                                              190                                                                              208                                                                              >11 10000                                                   194                                                                              93 130                                                                              136                                                                              138                                                                              144                                                                              10  100000                                                  195                                                                              103                                                                              114                                                                              125                                                                              127                                                                              136    100000                                                  196                                                                              102                                                                              97 102                                                                              92 104    100000                                                  197                                                                              87 89 91 81 52     100000                                                  198                                                                              94 97 112                                                                              99 85     10000                                                   199                                                                              105                                                                              104                                                                              96 83 61     100000                                                  200                                                                              97 109                                                                              107                                                                              120                                                                              88     5000                                                    201                                                                              89 117                                                                              91 69 52     100000                                                  202                                                                              98 108                                                                              110                                                                              116                                                                              128    279                                                     203                                                                              73 85 102                                                                              98 106    978                                                     204                                                                              79 109                                                                              105                                                                              101                                                                              109    3000                                                    205                                                                              92 115                                                                              140                                                                              141                                                                              138    263                                                     206                                                                              108                                                                              91 83 83 92     473                                                     209                   117                                                     213                   326                                                     214               0.87                                                        216                                                                              105                                                                              108                                                                              105                                                                              96 100    103                                                     217                                                                              86 87 91 72 52     102                                                     218                                                                              112                                                                              115                                                                              119                                                                              107                                                                              109    1984                                                    219                                                                              144                                                                              171                                                                              141                                                                              180                                                                              178    946  10000                                              229   104                                                                              86 99 114                                                            231   115                                                                              103                                                                              145                                                                              133                                                                              0.3                                                         232   110                                                                              115                                                                              115                                                                              121                                                            233   130                                                                              132                                                                              130                                                                              138                                                            234   95 84 84 111                                                            235   86 87 92 88                                                             236   109                                                                              102                                                                              106                                                                              115                                                            237   113                                                                              113                                                                              110                                                                              119                                                                              2.42                                                        240               10                                                          242                   12                                                      243   118                                                                              92 96 89                                                             244   119                                                                              134                                                                              129                                                                              144                                                            246                   114                                                     247   118                                                                              122                                                                              122                                                                              129                                                            248   142                                                                              130                                                                              140                                                                              149                                                            251                                                                              109                                                                              104                                                                              111                                                                              91 111                                                                              0.5                                                         252                                                                              75 86 79 97 86 >11 10000                                                   253                                                                              151                                                                              124                                                                              143                                                                              142                                                                              157                                                                              >11 688                                                     254                                                                              91 111                                                                              110                                                                              132                                                                              143                                                                              10  1340 10000                                              255                                                                              107                                                                              125                                                                              139                                                                              132                                                                              145                                                                              1.05                                                                              204                                                     256                                                                              97 100                                                                              104                                                                              128                                                                              116                                                                              1.4 95.5                                                    257                                                                              86 114                                                                              122                                                                              112                                                                              114                                                                              2.9 300                                                     258                                                                              107                                                                              107                                                                              108                                                                              107                                                                              98 10                                                          259                                                                              116                                                                              96 102                                                                              121                                                                              106                                                                              9                                                           260                                                                              100                                                                              115                                                                              105                                                                              99 90 >11                                                         261                                                                              98 105                                                                              95 100                                                                              111                                                                              6.6 131                                                     262                                                                              99 104                                                                              102                                                                              110                                                                              141                                                                              1.1 958                                                     263               0.73                                                        264               6.4                                                         265   110                                                                              112                                                                              112                                                                              115                                                            272                   329                                                     273                   3.4                                                     274                   204                                                     275   145                                                                              153                                                                              128                                                                              136                                                            276                   53.9                                                    278                   1.0  85      C                                          281                   0.02 10      C                                          282                   0.2  10.5    C                                          __________________________________________________________________________     .sup.1 Expressed in % increase in incorporation of .sup.3 Hthymidine over     control (100%)                                                                .sup.2 Binding affinity for the GABA.sub.A receptor from rat brain in         μM.                                                                        .sup.3 Binding affinity for the progestin receptor from rabbit uterus. in     nM.                                                                           .sup.4 Concentration to elicit a 200% increase in T47D Human breast cell      proliferation.                                                                .sup.5 Concentration to block the action of 0.15 nM R5020 by 50%              .sup.6 C = Active in Clauberg Assay; M = Active in McGinty Assay         

Additional Test to Determine Bone Growth Activity

Test compounds were orally administered once daily to mature femalerabbits for 12 weeks. Bone density was measured by dual X-raydensitometry and results were expressed as % base line bone mineralcontent.

Compounds 185 and 280 showed a significant increase in bone mineralcontent as compared to vehicle treated control.

I claim:
 1. Compounds effective as progestin agonists and having theformula: ##STR27## W is absent or --CH═CH--; R¹ are independentlyselected from the group consisting of halogen, --CF₃, and NO₂, or bothR¹ may be joined to form a bi-radical which is --CH═CHCH═CH--;R³ areindependently selected from the group consisting of hydrogen, C₁₋₆branched or linear alkyl, halogen and --CF₃, with the proviso that R³ atthe 3-position must be H when R³ at the 4-position is H, or both R³ maybe joined to form a bi-radical selected from the group consisting of--CH═CHCH═CH--, --C(NC₁₋₄ alkyl₂)═CHCH=CH-- and --(CH₂)₄ --; R⁵ isselected from the group consisting of H and Me;with the proviso thatonly one of R¹ and R³ forms the fused bi-radical; and the stereoisomersthereof.
 2. The compound of claim 1 wherein said A is 4-R¹, 3-R¹-phenyl.
 3. The compound of claim 1 where R³ is a mono-substituent atthe 4-position and selected from the group consisting of C₁₋₆ branchedor linear alkyl, halogen and --CF₃.
 4. A compound of claim 1 selectedfrom the group consisting of:3-(naphth-2-yl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-trifluoromethylbenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-chlorobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(2-naphthylenesulfonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-bromobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(4-methylbenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(4-chloro-3-trifluoromethylphenyl)-1-(4-trifluoromethylbenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(4-chloro-3-trifluoromethylphenyl)-1-(4-bromobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine; (R,S)3-(3,4-dichlorophenyl)-1-(4-iodobenzenesulphonyl)-6-methyl-1,4,5,6-tetrahydropyridazineand (R,S)3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulphonyl)-6-methyl-1,4,5,6-tetrahydropyridazine.5. Compounds effective as progestin antagonists and having the formula:##STR28## W is absent or --CH═CH--; R¹ is selected from the groupconsisting of halogen, --CF₃ and --NO₂, or both R¹ may be joined to forma bi-radical which is --CH═CHCH═CH--;R³ is hydrogen, halogen, --CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, carboxy C₁₋₄ alkyl and C₁₋₄ alkoxy carbonylC₁₋₄ alkoxy with the proviso that R³ at the 2-position is not hydrogen,or R³ may be joined to form a bi-radical which is --CH═CHCH═CH--attached at the 2- and 3-positions; R^(a) are independently selectedfrom hydrogen or halogen with the proviso that each may be halogen whenR³ is selected only from halogen; R⁵ is selected from the groupconsisting of hydrogen and methyl, or alternatively, R⁵ may be joinedwith the 6-position to form a bi-radical which is

    (5)-CH.sub.2 CH═CH-(6);

with the proviso that only one of R¹, R³ and R⁵ forms the fusedbi-radical; and the steroisomers and pharmaceutically acceptable saltsor esters thereof.
 6. The compound of claim 5 wherein said A is 4-R¹,3-R¹ -phenyl.
 7. The compound of claim 5 wherein R³ is amono-substitutent at the 2-position and selected from the groupconsisting of halogen CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, carboxy C₁₋₄ alkyland C₁₋₄ alkoxy carbonyl C₁₋₄ alkoxy.
 8. A compound of claim 5 selectedfrom the group consistingof:3-(3,4-dichlorophenyl)-1-(2,3-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(2,5-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(3,4-dichlorophenyl)-1-(2-(3-carbomethoxypropxy)-5-bromobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;3-(4-chloro-3-trifluoromethylphenyl)-1-(2,5-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydropyridazineand (R,S)3-(3,4-dichlorophenyl)-1-(2,5-dichlorobenzenesulphonyl)-5-methyl-1,4,5,6-tetrahydropyridazine.9. Compounds effective to promote bone cell growth and having theformula: ##STR29## Y is O or S; R³ is hydrogen or halogen with theproviso that at least two R³ are halogen;R⁵ is H or Me;and thesteroisomers thereof.
 10. The compound of claim 9 wherein said A isphenyl.
 11. The compound of claim 9 wherein R₃ is at the 3- and4-positions only.
 12. A compound of claim 9 selected from the groupconsistingof:1-(3,4-dichlorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine;1-(3,4-dichlorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine;1-(3,4-difluorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine;1-(3-bromo-4-fluorothiobenzoyl)-3-phenyl-1,4,5,6-1tetrahydropyridazine;(R,S)-(3,4-difluorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine;(R,S)-1-(3,4-dichlorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine;(R,S)-1-(3,4-dichlorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine;(R,S)-1-(3,4-difluorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine1-(3,4-dichlorobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine;1-(3,4-dichlorobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine;1-(3,4-dichlorothiobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazineand1-(3,4-dichlorothiobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine.